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Previous studies examining structural brain correlates of irritability have taken a region-specific approach and have been relatively inconsistent. In a sample of adolescents with and without clinically impairing irritability, the current study examines: (i) cortical volume (CV) in canonical functional networks; (ii) the association between the CV of functional networks and severity of irritability; and (iii) the extent to which IQ mediates the association between structural abnormalities and severity of irritability. Structural MRI and IQ data were collected from 130 adolescents with high irritability (mean age = 15.54±1.83 years, 58 females, self-reported Affective Reactivity Index [ARI] ≥ 4) and 119 adolescents with low irritability (mean age = 15.10±1.93 years, 39 females, self-reported ARI < 4). Subject-specific network-wise CV was estimated after parcellating the whole brain into 17 previously reported functional networks. Our Multivariate Analysis of Covariance (MANCOVA) revealed that adolescents with high irritability had significantly reduced CV of the bilateral control and default-mode networks (p

Objective: A preliminary investigation of the impact of a serotonergic agent (fluoxetine) on symptom profile and neural response in youths with disruptive behavior disorders (DBDs) and a history of trauma exposure. Methods: There were three participant groups: (i) Youths with DBDs and trauma exposure who received fluoxetine treatment for 8 weeks (n = 11); (ii) A matched group of youths with DBDs and trauma exposure who received routine regular follow-up in an outpatient clinic (n = 10); and (iii) Typically developing youths (n = 18). All participants conducted an expression processing functional magnetic resonance imaging task twice, 8 weeks apart: (pretreatment and post-treatment for youths with DBDs). Results: Youths with DBDs and trauma exposure who received fluoxetine treatment compared to the other two groups showed: (i) significant improvement in externalizing, oppositional defiant disorder, irritability, anxiety-depression, and trauma-related symptoms; (ii) as a function of fearful expression intensity, significantly decreased amygdala response and increased recruitment of regions implicated in top-down attention control (insula cortex, inferior parietal lobule, and postcentral gyrus) and emotional regulation (ventromedial prefrontal cortex [vmPFC]); and (iii) correlation between DBD/irritability symptom improvement and increased activation of top-down attention control areas (inferior parietal lobule, insula cortex, and postcentral gyrus) and an emotion regulation area (vmPFC). Conclusions: This study provides preliminary evidence that a serotonergic agent (fluoxetine) can reduce disruptive behavior and mood symptoms in youths with DBDs and trauma exposure and that this may be mediated by enhanced activation of top-down attention control and emotion regulation areas (inferior parietal lobule, insula cortex, and vmPFC).

Objectives: Temporal reward discounting impulsivity (TDI) reflects a propensity to choose smaller immediate rather than larger delayed rewards relative to age/IQ-matched peers. Previous work with adults has linked TDI to an increased risk for antisocial behavior but also psychopathology in general. However, little work has examined TDI in adolescents with conduct disorder (CD), or considered whether TDI might be associated dimensionally with traits associated with antisocial behavior, that is, impulsivity, irritability, and/or callous–unemotional traits. In this study TDI was investigated in a large adolescent group with varying levels of antisocial behavior. Methods: Participants consisted of 195 adolescents (67 with CD, 77 in a psychiatric comparison group and 51 typically developing adolescents). Participants performed a temporal discounting task and individual differences were measured through the Connors rating scale for attention-deficit/hyperactivity disorder (impulsivity), Affective Reactivity Index (irritability), and Inventory of Callous–Unemotional traits. Results: The adolescents with CD and those in the psychiatric comparison group showed significantly greater TDI than typically developing adolescents. However, these group differences were abolished when dimensional covariates were included. Irritability was significantly associated with TDI. Conclusions: We conclude that TDI reflects a transdiagnostic form of dysfunction that particularly manifests in adolescents with increased irritability.

Although both pediatric and adult patients with anxiety disorders exhibit similar neural responding to threats, age-related differences have been found in some functional MRI (fMRI) studies. To reconcile disparate findings, the authors compared brain function in youths and adults with and without anxiety disorders while rating fear and memory of ambiguous threats.Two hundred medication-free individuals ages 8-50 were assessed, including 93 participants with an anxiety disorder. Participants underwent discriminative threat conditioning and extinction in the clinic. Approximately 3 weeks later, they completed an fMRI paradigm involving extinction recall, in which they rated their levels of fear evoked by, and their explicit memory for, morph stimuli with varying degrees of similarity to the extinguished threat cues.Age moderated two sets of anxiety disorder findings. First, as age increased, healthy subjects compared with participants with anxiety disorders exhibited greater amygdala-ventromedial prefrontal cortex (vmPFC) connectivity when processing threat-related cues. Second, age moderated diagnostic differences in activation in ways that varied with attention and brain regions. When rating fear, activation in the vmPFC differed between the anxiety and healthy groups at relatively older ages. In contrast, when rating memory for task stimuli, activation in the inferior temporal cortex differed between the anxiety and healthy groups at relatively younger ages.In contrast to previous studies that demonstrated age-related similarities in the biological correlates of anxiety disorders, this study identified age differences. These findings may reflect this study's focus on relatively late-maturing psychological processes, particularly the appraisal and explicit memory of ambiguous threat, and inform neurodevelopmental perspectives on anxiety.

Objectives Bipolar disorder (BD) and familial risk for BD have been associated with aberrant white matter (WM) microstructure in the corpus callosum and fronto-limbic pathways. These abnormalities might constitute trait or state marker and have been suggested to result from aberrant maturation and to relate to difficulties in emotion regulation. Methods To determine whether WM alterations represent a trait, disease or resilience marker, we compared youth at risk for BD (n = 36 first-degree relatives, REL) to youth with BD (n = 36) and healthy volunteers (n = 36, HV) using diffusion tensor imaging. Results Individuals with BD and REL did not differ from each other in WM microstructure and, compared to HV, showed similar aberrations in the superior corona radiata (SCR)/corticospinal tract (CST) and the body of the corpus callosum. WM microstructure of the anterior CC showed reduced age-related in-creases in BD compared to REL and HV. Further, individuals with BD and REL showed in-creased difficulties in emotion regulation, which were associated with the microstructure of the anterior thalamic radiation. Discussion Alterations in the SCR/CST and the body of the corpus callosum appear to represent a trait marker of BD, whereas changes in other WM tracts seem to be a disease state marker. Our findings also support the role of aberrant developmental trajectories of WM microstructure in the risk architecture of BD, although longitudinal studies are needed to confirm this association. Finally, our findings show the relevance of WM microstructure for difficulties in emotion regulation-a core characteristic of BD.

The goal of this study was to compare brain structure between individuals with generalized anxiety disorder (GAD) and healthy controls. Previous studies have generated inconsistent findings, possibly due to small sample sizes, or clinical/analytic heterogeneity. To address these concerns, we combined data from 28 research sites worldwide through the ENIGMA-Anxiety Working Group, using a single, pre-registered mega-analysis. Structural magnetic resonance imaging data from children and adults (5–90 years) were processed using FreeSurfer. The main analysis included the regional and vertex-wise cortical thickness, cortical surface area, and subcortical volume as dependent variables, and GAD, age, age-squared, sex, and their interactions as independent variables. Nuisance variables included IQ, years of education, medication use, comorbidities, and global brain measures. The main analysis (1020 individuals with GAD and 2999 healthy controls) included random slopes per site and random intercepts per scanner. A secondary analysis (1112 individuals with GAD and 3282 healthy controls) included fixed slopes and random intercepts per scanner with the same variables. The main analysis showed no effect of GAD on brain structure, nor interactions involving GAD, age, or sex. The secondary analysis showed increased volume in the right ventral diencephalon in male individuals with GAD compared to male healthy controls, whereas female individuals with GAD did not differ from female healthy controls. This mega-analysis combining worldwide data showed that differences in brain structure related to GAD are small, possibly reflecting heterogeneity or those structural alterations are not a major component of its pathophysiology.

Background Early childhood social reticence (SR) and preadolescent social anxiety (SA) symptoms increase the risk for more severe SA in later adolescence. Yet, not all at-risk youth develop more severe SA. The emergence of distinct patterns of neural response to socially evocative contexts during pivotal points in development may help explain this discontinuity. We tested the extent to which brain function during social interactions in preadolescence influenced the effects of SA and early childhood SR on predicting SA symptoms in midadolescence. Methods Participants (N = 53) were assessed for SR from ages 2 to 7. At age 11, SA symptoms were assessed and brain function was measured using functional magnetic resonance imaging (fMRI) as participants anticipated social evaluation from purported peers with a reputation for being unpredictable, nice, and mean. At age 13, SA symptoms were re-assessed. Moderated-mediation models tested the extent to which early childhood SR, preadolescent SA, and preadolescent brain function predicted midadolescent SA. Results In individuals with preadolescent SA, the presence of early childhood SR and SR-linked differences in brain activation predicted more severe SA in midadolescence. Specifically, in those who exhibited preadolescent SA, greater early childhood SR was associated with enhanced bilateral insula engagement while anticipating unpredictable-versus-nice social evaluation in preadolescence, and more severe SA in midadolescence. Conclusions SR-linked neural responses to socially evocative peer interactions may predict more severe SA symptoms in midadolescence among individuals with greater preadolescent SA symptoms and childhood SR. This same pattern of neural response may not be associated with more severe SA symptoms in youth with only one risk factor.

Irritability and anxiety are two common clinical phenotypes that involve high-arousal negative affect states (anger and fear), and that frequently co-occur. Elucidating how these two forms of emotion dysregulation relate to perturbed neurodevelopment may benefit from alternate phenotyping strategies. One such strategy applies a bifactor latent variable approach that can parse shared versus unique mechanisms of these two phenotypes. Here, we aim to replicate and extend this approach and examine associations with neural structure in a large transdiagnostic sample of youth (N= 331;M= 13.57,SD= 2.69 years old; 45.92% male). FreeSurfer was used to extract cortical thickness, cortical surface area, and subcortical volume. The current findings replicated the bifactor model and demonstrate measurement invariance as a function of youth age and sex. There were no associations of youth's factor scores with cortical thickness, surface area, or subcortical volume. However, we found strong convergent and divergent validity between parent-reported irritability and anxiety factors with clinician-rated symptoms and impairment. A general negative affectivity factor was robustly associated with overall functional impairment across symptom domains. Together, these results support the utility of the bifactor model as an alternative phenotyping strategy for irritability and anxiety, which may aid in the development of targeted treatments.

OBJECTIVES Little is known about potential differences in the pathophysiology of bipolar disorder (BD) across development. The present study aimed to characterize age-related neural mechanisms of BD. METHODS Youths and adults with and without BD (N = 108, age range = 9.8-55.9 years) completed an emotional face labeling task during fMRI acquisition. We leveraged three different fMRI analytic tools to identify age-related neural mechanisms of BD, investigating (a) change in neural responses over the course of the task, (b) neural activation averaged across the entire task, and (c) amygdala functional connectivity. RESULTS We found converging Age Group × Diagnosis patterns across all three analytic methods. Compared to healthy youths vs adults, youths vs adults with BD show an altered pattern in response to repeated presentation of emotional faces in medial prefrontal, amygdala, and temporoparietal regions, as well as amygdala-temporoparietal connectivity. Specifically, medial prefrontal and lingual activation decreases over the course of repeated emotional face presentations in healthy youths vs adults but increases in youths with BD compared to adults with BD. Moreover, youths vs adults with BD show less medial prefrontal activation and amygdala-temporoparietal junction connectivity averaged over the task, but this difference is not found for healthy youths vs adults. CONCLUSION Although longitudinal confirmation and replication will be necessary, these findings suggest that neural development may be aberrant in BD and that some neural mechanisms mediating BD may differ in adults vs children with the illness.

Attention-deficit/hyperactivity disorder (ADHD) and depression commonly co-occur. Identifying children with ADHD at risk for later depression may allow early intervention and prevention. Irritability is one possible mechanism linking these two disorders. It is common in ADHD and associated with later depression in the general population. Cross-sectional studies suggest an association between irritability and depression in ADHD, but longitudinal research is limited. This study followed up a clinical ADHD sample longitudinally to examine: (1) the association between childhood irritability and later depression symptoms, and (2) whether irritability persistence is important in this association. At baseline, parents (n = 696) completed semi-structured interviews about their child (mean age = 10.9), providing information on child psychopathology, including irritability. A subsample (n = 249) was followed up after a mean of 5.4 years. Parent-completed Mood and Feelings Questionnaires provided information on depressive symptoms at follow-up. Parent-rated structured diagnostic interviews provided information on ADHD diagnosis and irritability at follow-up. Regression analyses examined associations between (i) baseline irritability and depression symptoms at follow-up, and (ii) persistent (vs. remitted) irritability and depression symptoms at follow-up. Analyses controlled for age, gender, depression symptoms, anxiety, ADHD symptoms, and ADHD medication at baseline. Baseline irritability was associated with depression symptoms at follow-up, but the association attenuated after controlling for anxiety and ADHD symptoms. Persistent irritability was associated with depression symptoms at follow-up, after including all covariates. Children with ADHD with persistent irritability are at elevated risk of developing depression symptoms. They may be a target for early intervention and prevention of depression. Electronic supplementary material The online version of this article (10.1007/s00787-019-01303-x) contains supplementary material, which is available to authorized users.

Background Callous-Unemotional (CU) and psychopathic traits are consistently associated with impaired recognition of others' emotions, specifically fear and sadness. However, no studies have examined whether the association between CU traits and emotion recognition deficits is due primarily to genetic or environmental factors. Methods The current study used data from 607 Caucasian twin pairs (N = 1,214 twins) to examine the phenotypic and genetic relationship between the Inventory of Callous-Unemotional Traits (ICU) and facial emotion recognition assessed via the laboratory-based Facial Expression Labeling Task (FELT). Results The uncaring/callous dimension of the ICU was significantly associated with impaired recognition of happiness, sadness, fear, surprise, and disgust. The unemotional ICU dimension was significantly associated with improved recognition of surprise and disgust. Total ICU score was significantly associated with impaired recognition of sadness. Significant genetic correlations were found for uncaring/callous traits and distress cue recognition (i.e. fear and sadness). The observed relationship between uncaring/callous traits and deficits in distress cue recognition was accounted for entirely by shared genetic influences. Conclusions The results of the current study replicate previous findings demonstrating impaired emotion recognition among youth with elevated CU traits. We extend these findings by replicating them in an epidemiological sample not selected or enriched for pathological levels of CU traits. Furthermore, the current study is the first to investigate the genetic and environmental etiology of CU traits and emotion recognition, and results suggest genetic influences underlie the specific relationship between uncaring/callous traits and distress cue (fear/sadness) recognition in others.

This study uses novel approaches to examine genetic and environmental influences shared between childhood behavioral inhibition (BI) and symptoms of preadolescent anxiety disorders. Three hundred and fifty-two twin pairs aged 9–13 and their mothers completed questionnaires about BI and anxiety symptoms. Biometrical twin modeling, including a direction-of-causation design, investigated genetic and environmental risk factors shared between BI and social, generalized, panic and separation anxiety. Social anxiety shared the greatest proportion of genetic (20%) and environmental (16%) variance with BI with tentative evidence for causality. Etiological factors underlying BI explained little of the risk associated with the other anxiety domains. Findings further clarify etiologic pathways between BI and anxiety disorder domains in children.

BackgroundAberrations in reward and penalty processing are implicated in depression and putatively reflect altered dopamine signalling. This study exploits the advantages of a placebo-controlled design to examine how a novel D2 antagonist with adjunctive antidepressant properties modifies activity in the brain's reward network in depression.MethodsWe recruited 43 medication-naïve subjects across the range of depression severity (Beck's Depression Inventory-II score range: 0–43), including healthy volunteers, as well as people meeting full-criteria for major depressive disorder. In a double-blind placebo-controlled cross-over design, all subjects received either placebo or lurasidone (20 mg) across two visits separated by 1 week. Functional magnetic resonance imaging with the Monetary Incentive Delay (MID) task assessed reward functions via neural responses during anticipation and receipt of gains and losses. Arterial spin labelling measured cerebral blood flow (CBF) at rest.ResultsLurasidone altered fronto-striatal activity during anticipation and outcome phases of the MID task. A significant three-way Medication-by-Depression severity-by-Outcome interaction emerged in the anterior cingulate cortex (ACC) after correction for multiple comparisons. Follow-up analyses revealed significantly higher ACC activation to losses in high- v. low depression participants in the placebo condition, with a normalisation by lurasidone. This effect could not be accounted for by shifts in resting CBF.ConclusionsLurasidone acutely normalises reward processing signals in individuals with depressive symptoms. Lurasidone's antidepressant effects may arise from reducing responses to penalty outcomes in individuals with depressive symptoms.

Mapping individual differences in behavior is fundamental to personalized neuroscience, but quantifying complex behavior in real world settings remains a challenge. While mobility patterns captured by smartphones have increasingly been linked to a range of psychiatric symptoms, existing research has not specifically examined whether individuals have person-specific mobility patterns. We collected over 3000 days of mobility data from a sample of 41 adolescents and young adults (age 17-30 years, 28 female) with affective instability. We extracted summary mobility metrics from GPS and accelerometer data and used their covariance structures to identify individuals and calculated the individual identification accuracy-i.e., their "footprint distinctiveness". We found that statistical patterns of smartphone-based mobility features represented unique "footprints" that allow individual identification (p 0.001). Critically, mobility footprints exhibited varying levels of person-specific distinctiveness (4-99%), which was associated with age and sex. Furthermore, reduced individual footprint distinctiveness was associated with instability in affect (p 0.05) and circadian patterns (p 0.05) as measured by environmental momentary assessment. Finally, brain functional connectivity, especially those in the somatomotor network, was linked to individual differences in mobility patterns (p 0.05). Together, these results suggest that real-world mobility patterns may provide individual-specific signatures relevant for studies of development, sleep, and psychopathology.

Background: Threat anticipation engages neural circuitry that has evolved to promote defensive behaviours; perturbations in this circuitry could generate excessive threat-anticipation response, a key characteristic of pathological anxiety. Research into such mechanisms in youth faces ethical and practical limitations. Here, we use thermal stimulation to elicit pain-anticipatory psychophysiological response and map its correlates to brain structure among youth with anxiety and healthy youth. Methods: Youth with anxiety (n = 25) and healthy youth (n = 25) completed an instructed threat-anticipation task in which cues predicted nonpainful or painful thermal stimulation; we indexed psychophysiological response during the anticipation and experience of pain using skin conductance response. High-resolution brain-structure imaging data collected in another visit were available for 41 participants. Analyses tested whether the 2 groups differed in their psychophysiological cue-based pain-anticipatory and pain-experience responses. Analyses then mapped psychophysiological response magnitude to brain structure. Results: Youth with anxiety showed enhanced psychophysiological response specifically during anticipation of painful stimulation (b = 0.52, p = 0.003). Across the sample, the magnitude of psychophysiological anticipatory response correlated negatively with the thickness of the dorsolateral prefrontal cortex (pFWE < 0.05); psychophysiological response to the thermal stimulation correlated positively with the thickness of the posterior insula (pFWE < 0.05). Limitations: Limitations included the modest sample size and the cross-sectional design. Conclusion: These findings show that threat-anticipatory psychophysiological response differentiates youth with anxiety from healthy youth, and they link brain structure to psychophysiological response during pain anticipation and experience. A focus on threat anticipation in research on anxiety could delineate relevant neural circuitry.

Influential theories implicate variations in the mechanisms supporting threat learning in the severity of anxiety symptoms. We use computational models of associative learning in conjunction with structural imaging to explicate links among the mechanisms underlying threat learning, their neuroanatomical substrates, and anxiety severity in humans. We recorded skin-conductance data during a threat-learning task from individuals with and without anxiety disorders (N=251; 8-50 years; 116 females). Reinforcement-learning model variants quantified processes hypothesized to relate to anxiety: threat conditioning, threat generalization, safety learning, and threat extinction. We identified the best-fitting models for these processes and tested associations among latent learning parameters, whole-brain anatomy, and anxiety severity. Results indicate that greater anxiety severity related specifically to slower safety learning and slower extinction of response to safe stimuli. Nucleus accumbens gray-matter volume moderated learning-anxiety associations. Using a modeling approach, we identify computational mechanisms linking threat learning and anxiety severity and their neuroanatomical substrates.

Introduction Irritability has both mood and behavioral manifestations. These frequently co-occur, and it is unclear to what extent they are dissociable domains. We used confirmatory factor analysis and external validators to investigate the independence of mood and behavioral components of irritability. Methods The sample comprised 246 patients (mean age 45 years; 63% female) from four outpatient programs (depression, anxiety, bipolar, and schizophrenia) at a tertiary hospital. A clinical instrument rated by trained clinicians was specifically designed to capture irritable mood and disruptive behavior dimensionally, as well as current categorical diagnoses i.e., intermittent explosive disorder (IED); oppositional defiant disorder (ODD); and an adaptation to diagnose disruptive mood dysregulation disorder (DMDD) in adults. Confirmatory factor analysis (CFA) was used to test the best fitting irritability models and regression analyses were used to investigate associations with external validators. Results Irritable mood and disruptive behavior were both frequent, but diagnoses of disruptive syndromes were rare (IED, 8%; ODD, 2%; DMDD, 2%). A correlated model with two dimensions, and a bifactor model with one general dimension and two specific dimensions (mood and behavior) both had good fit indices. The correlated model had root mean square error of approximation (RMSEA) = 0.077, with 90% confidence interval (90%CI) = 0.071-0.083; comparative fit index (CFI) = 0.99; and Tucker-Lewis index (TLI) = 0.99, while the bifactor model had RMSEA = 0.041; CFI = 0.99; and TLI = 0.99 respectively). In the bifactor model, external validity for differentiation of the mood and behavioral components of irritability was also supported by associations between irritable mood and impairment and clinical measures of depression and mania, which were not associated with disruptive behavior. Conclusions Psychometric and external validity data suggest both overlapping and specific features of the mood vs. disruptive behavior dimensions of irritability.

Cognitive-behavioral therapy (CBT), a first-line treatment for pediatric anxiety disorders, is based on principles of threat learning and extinction. However, CBT does not work sufficiently for up to 40% of clinically anxious youth. The neural and behavioral correlates of conditioned inhibition might provide promising targets for attempts to improve CBT response. During conditioned inhibition, threat and safety cues appear together, forming a safety compound. Here, we test whether this safety compound elicits a reduced fear response compared to pairing the threat cue with a novel cue (novel compound). The current pilot study compares behavioral, physiological, and neural correlates of conditioned inhibition between children with (n = 17, Mage = 13.09, SDage = 3.05) and without (n = 18, Mage = 14.49, SDage = 2.38) anxiety disorders. Behavioral and physiological measures did not differ between children with and without anxiety disorders during fear acquisition. During testing, children with anxiety disorders showed overall higher skin conductance response and expected to hear the aversive sound following the novel compound more often than children without anxiety disorders. Children with anxiety disorders showed more activity in the right ventromedial prefrontal cortex (vmPFC) to the safety versus novel compound. Children without anxiety disorders showed the opposite pattern – more right vmPFC activity to the novel versus safety compound (F(1,31) = 5.40, p = 0.03). No group differences manifested within the amygdala, dorsal anterior cingulate cortex, or hippocampus. These pilot findings suggest a feasible approach for examining conditioned inhibition in pediatric anxiety disorders. If replicated in larger samples, findings may implicate perturbed conditioned inhibition in pediatric anxiety disorders and provide targets for CBT.

Irritability is common in Attention-Deficit Hyperactivity Disorder (ADHD), but little is known about whether irritability predicts the course of ADHD symptoms over time. Adolescence is a dynamic period of emotional development as well as shifts in ADHD symptoms; an important goal is to identify youth at risk of increasing or persisting symptoms. We examined irritability as a longitudinal predictor of change in adolescents’ ADHD symptoms, as well as how this link may differ in females versus males. The sample included 108 youth (72 males) age 12–16 years (M = 14.21 years, SD = 1.44 years), 62 of whom met criteria for ADHD. Approximately 18 months later, 80 participants (48 males) were followed up at Time 2. A dimensional approach was used to examine changes over time in parent-reported inattentive and hyperactive/impulsive symptoms. Longitudinal path analysis revealed that irritability at Time 1 predicted higher relative hyperactive/impulsive symptoms at Time 2 after controlling for age and longitudinal stability in all variables. A multiple-group analysis examining moderation by sex/gender revealed that this association was significant only for females. These results suggest that irritability may play a key role in the persistence and worsening of hyperactive/impulsive symptoms across adolescence for females, with potential implications for the diagnosis and treatment of females with ADHD.

Attentional control theory suggests that high cognitive demands impair the flexible deployment of attention control in anxious adults, particularly when paired with external threats. Extending this work to pediatric anxiety, we report two studies utilizing eye tracking (Study 1) and functional magnetic resonance imaging (Study 2). Both studies use a visual search paradigm to examine anxiety-related differences in the impact of threat on attentional control at varying levels of task difficulty. In Study 1, youth ages 8–18 years (N=109), completed the paradigm during eye tracking. Results indicated that youth with more severe anxiety took longer to fixate on and identify the target, specifically on difficult trials, compared to youth with less anxiety. However, no anxiety-related effects of emotional distraction (faces) emerged. In Study 2, a separate cohort of 8–18-year-olds (N=72) completed a similar paradigm during fMRI. Behaviorally, youth with more severe anxiety were slower to respond on searches following non-threatening, compared to threatening, distractors, but this effect did not vary by task difficulty. The same interaction emerged in the neuroimaging analysis in the superior parietal lobule and precentral gyrus-more severe anxiety was associated with greater brain response following non-threatening distractors. Theoretical implications of these inconsistent findings are discussed.

The Affective Reactivity Index (ARI) is an irritability measure with good psychometric properties. However, there are no published studies in preschool children, an important population in which to differentiate normative from non-normative irritability. The goal of this study was to validate the ARI in preschoolers. Two samples were included: a school-based sample (N = 487, mean age = 57.80 ± 7.23 months, 52.8% male) and a clinical sample of children with Attention Deficit Hyperactivity Disorder (ADHD; N = 153, mean age = 60.5 ± 7.6 months, 83.7% males). Confirmatory factor analysis assessed ARI unidimensionality. ARI criterion validity was tested through comparison to other scales measuring irritability, related constructs, and other aspects of psychopathology. Test-retest reliability was assessed in the school-based sample. Analyses confirmed a single-factor structure and good internal consistency. The ARI showed stronger correlations with irritability measures than with measures of other constructs. In the clinical sample, ADHD children with comorbid disruptive behavior disorders had higher ARI scores than those without this comorbidity. In the school-based sample, test-retest reliability was moderate. This is the first study to demonstrate ARI validity and reliability in preschoolers. The scale performed well in both school-based and clinical samples. Having a concise and validated irritability measure for preschoolers may facilitate both clinical assessment and research on early irritability.

Highlights • Brain response to social feedback varies by age and social anxiety severity in youth. • Younger, anxious youth show greater activation to unpredictable negative feedback. • Different associations emerge among older, anxious adolescents., Adolescence is a sensitive period for the development of adaptive social behaviors and social anxiety, possibly due to aspects of brain development. However, research is needed to examine interactions among age, social anxiety, and social dynamics previously shown to influence neural responding. The current functional magnetic resonance imaging (fMRI) study examines brain function in 8–18 year-olds with varying levels of social anxiety. Interactions are examined among age, social anxiety, and two key task factors: valence and predictability of social interactions. Results demonstrate age, social anxiety severity, and each of the two key task-based factors interact to predict neural response in the caudate, middle and superior temporal gyri. In particular, among adolescents less-than 13 years of age, higher social anxiety predicted greater responding to unpredictable negative evaluations. However, in this same age group, the opposite pattern emerged during receipt of unpredictable positive evaluations, with less neural response in more anxious youth. Adolescents aged 13 and older overall showed less robust effects. We discuss these findings in terms of age- and anxiety-related differences in socioemotional processing.

Objective: Despite the advances in the field of neuroscience, many questions remain regarding the mechanisms of anxiety, as well as moderators of treatment outcome. Long-term adverse outcomes for anxious youth may relate to pathophysiologically based information processing patterns and self-referential beliefs, such as self-efficacy. In fact, there are no studies highlighting the relationship between self-efficacy and neurocircuitry in youth. The purpose of this study was to explore the relationships between self-efficacy, brain morphometry, and youth anxiety. Methods: Parent, child, and clinician ratings of anxiety symptoms and child-reported self-efficacy were analyzed in a sample of 8- to 17-year-old youth (n = 51). Measures were collected from all youth at baseline and during and after treatment for the patients. Anxious patients (n = 26) received 12 sessions of cognitive behavioral therapy (CBT). Moreover, imaging data obtained from all participants before treatment were utilized in analyses. Results: Patients reported lower self-efficacy than healthy volunteers. Across the entire sample, anxiety was negatively related to total, social, and emotional efficacy. Both social and emotional efficacy predicted anxiety posttreatment. In addition, social efficacy predicted social anxiety symptoms posttreatment and social efficacy increased across treatment. There were no significant relations between self-efficacy and neurocircuitry. Conclusions: Self-efficacy is an important treatment target for anxious youth. Although self-efficacy was not related to brain morphometry, self-efficacy beliefs may constitute an important mechanism through which CBT and psychopharmacological interventions decrease fear and anxiety symptoms in youth.

OBJECTIVE: Naturalistic studies suggest that expectation of adverse experiences such as pain exerts particularly strong effects on anxious youth. In healthy adults, expectation influences the experience of pain. The current study uses experimental methods to compare the effects of expectation on pain among adults, healthy youth, and youth with an anxiety disorder. METHODS: Twenty-three healthy adults, 20 healthy youth, and 20 youth with an anxiety disorder underwent procedures in which auditory cues were paired with noxious thermal stimulation. Through instructed conditioning, one cue predicted low pain stimulation and the other predicted high pain stimulation. At test, each cue was additionally followed by a single temperature calibrated to elicit medium pain ratings. We compared cue-based expectancy effects on pain across the three groups, based on cue effects on pain elicited on medium heat trials. RESULTS: Across all groups, as expected, participants reported greater pain with increasing heat intensity (β = 2.29, t(41) = 29.94, p < .001). Across all groups, the critical medium temperature trials were rated as more painful in the high-relative to low-expectancy condition (β = 1.72, t(41) = 10.48, p < .001). However, no evidence of between-group differences or continuous associations with age or anxiety were observed. CONCLUSIONS: All participants showed strong effects of expectancy on pain. No influences of development or anxiety arose. Complex factors may influence associations among anxiety, development, and pain reports in naturalistic studies. Such factors may be identified using experiments that employ more complex, yet controlled manipulations of expectancy or assess neural correlates of expectancy.

Objective: Socially anxious adolescents report distress during social decision-making, wherein their favorable view of peers directly conflicts with their expectation to be viewed negatively by peers; a phenomenon we refer to as “mismatch bias.” The present study utilizes a novel paradigm with dynamic social stimuli to explore the correlates of mismatch biases in anxious and healthy youth. Method: The behavioral and neural correlates of mismatch biases were assessed in healthy (N = 17) and anxious (N = 14) youth during functional MRI. Participants completed a novel task where they viewed silent videos of unknown peers. After viewing each video, participants appraised the social desirability of the peer (“How much do you think you would like them [if you met them]”) or predicted how socially desirable the peer would find them (“How much do you think they would like you [if you met them]”). Each participant's mismatch bias was calculated as the difference between their appraisal of peers and their prediction of peers' appraisal of them. Results: We found that anxious youth exhibited mismatch bias: they rated unknown peers as more desirable than they predicted peers would rate them. This effect was not present in the healthy group. Mismatch biases were associated with increased engagement of the ventrolateral prefrontal cortex (vlPFC), a region broadly involved in flexible cognitions and behavioral selection. In addition, greater mismatch biases and vlPFC activation during mismatch biases were associated with more severe anxiety symptoms. Conclusions: The findings highlight the importance of understanding mismatch biases to inform treatments that target distress elicited by discrepant social appraisals in anxious youth.

OBJECTIVE: Childhood irritability exhibits significant theoretical and empirical associations with depression and anxiety syndromes. The current study used the twin design to parse genetic and environmental contributions to these relationships. METHOD: Children aged 9–14 from 374 twin pairs were assessed for irritability and symptoms of depression, generalized anxiety, panic, social phobia, and separation anxiety using dimensional self-report instruments. Multivariate structural equation modeling decomposed the correlations between these syndromes into genetic and environmental components to examine shared and specific risk domains. RESULTS: Irritability had significant associations with each internalizing symptom domain. Genetic contributions to irritability are moderately correlated with genetic risk for symptoms of depression, generalized anxiety, and separation anxiety with weaker overlap with the other anxiety syndromes. Familial and specific environmental risk factors explained covariation among syndromes and indicated potential syndrome-specific risk. CONCLUSIONS: There is substantial overlap among the genetic and environmental factors that influence individual differences in irritability and those that increase liability for depression and anxiety symptoms in children. These findings deepen the current understanding of childhood internalizing risk factors and provide important implications for syndrome prediction and susceptibility gene discovery efforts.

Irritability is a prominent feature of chronic mental disorders and a developmental marker of their early emergence. The most salient feature of irritability in early childhood is temper tantrums. While temper tantrums are normative in young children, they can be clinically concerning when they are dysregulated, very frequent, and/or occur in unexpected contexts. The present study uses behavioral and event-related brain potential (ERP) measures to characterize the relationship between irritability and neural markers of response inhibition in very young children. Forty-six children (ages 4–7 years) completed a go/no-go task under nonfrustrating and frustrating conditions. ERPs elicited by go and no-go stimuli were examined as a function of frustration condition and irritability, operationalized via the well-validated Temper Loss scale of the Multidimensional Assessment Profile of Disruptive Behavior (MAP-DB). Higher Temper Loss scores were associated with larger N2(no-go) amplitudes and reduced no-go accuracy during frustration. This suggests that higher levels of irritability corresponded with increased conflict monitoring and poorer task performance during frustration. These findings add to a developing literature identifying the neurocognitive markers of varying levels of irritability in young children.

Reward Prediction Errors (RPEs), defined as the difference between the expected and received outcomes, are integral to reinforcement learning models and play an important role in development and psychopathology. In humans, RPE encoding can be estimated using fMRI recordings, however, a basic measurement property of RPE signals, their test-retest reliability across different time scales, remains an open question. In this paper, we examine the 3-month and 3-year reliability of RPE encoding in youth (mean age at baseline = 10.6 ± 0.3 years), a period of developmental transitions in reward processing. We show that RPE encoding is differentially distributed between the positive values being encoded predominantly in the striatum and negative RPEs primarily encoded in the insula. The encoding of negative RPE values is highly reliable in the right insula, across both the long and the short time intervals. Insula reliability for RPE encoding is the most robust finding, while other regions, such as the striatum, are less consistent. Striatal reliability appeared significant as well once covarying for factors, which were possibly confounding the signal to noise ratio. By contrast, task activation during feedback in the striatum is highly reliable across both time intervals. These results demonstrate the valence-dependent differential encoding of RPE signals between the insula and striatum, and the consistency of RPE signals or lack thereof, during childhood and into adolescence. Characterizing the regions where the RPE signal in BOLD fMRI is a reliable marker is key for estimating reward-processing alterations in longitudinal designs, such as developmental or treatment studies.

Face emotion imaging paradigms are widely used in both healthy and psychiatric populations. Here, in children and adolescents, we evaluate the test-retest reliability of blood oxygenation-level dependent (BOLD) activation and task-based functional connectivity on a widely used implicit face emotion processing task (i.e., gender labeling). Twenty-five healthy youth (M age = 13.97 year s; 60% female) completed two functional magnetic resonance imaging (fMRI) scan sessions approximately two months apart. Participants identified the gender of faces displaying angry, fearful, happy, and neutral emotions. A Bayesian adaptation of the intraclass correlation (ICC) assessed reliability of evoked BOLD activation and amygdala seed-based functional connectivity on task events vs. baseline as well as contrasts between face emotions. For each face emotion vs. baseline, good reliability of activation was demonstrated across key emotion processing regions including middle, medial, and inferior frontal gyri. However, contrasts between face emotions yielded variable results. Contrasts of angry to neutral or happy faces exhibited good reliability of amygdala connectivity to prefrontal regions. Contrasts of fearful to happy faces exhibited good reliability of activation in the anterior cingulate. Findings inform the reproducibility literature and emphasize the need for continued evaluation of task reliability.

Background Youth with chronic irritability and excessive reactivity, diagnosed as disruptive mood dysregulation disorder (DMDD), have social impairment in multiple settings (i.e., peers, school, and home). This paper presents a pilot randomized trial assessing the feasibility, acceptability, and preliminary efficacy of interpersonal psychotherapy (IPT) for mood and behavior dysregulation (IPT-MBD), an adapted version of IPT for depressed adolescents. IPT-MBD focuses on decreasing outbursts and irritability and improving interpersonal interactions. Methods Nineteen adolescents (aged 12-17) with DMDD or its research precursor, severe mood dysregulation, were randomly assigned to IPT-MBD (n = 10) or treatment-as-usual (TAU, n = 9) in a 24-week psychosocial intervention study. Assessments of mood symptoms and overall functioning were conducted by an independent evaluator, blinded to treatment, every 4 weeks. Parent and self-report irritability measures were collected every 4 weeks. Results Eighty percent of participants randomized to the IPT-MBD arm completed the study. Also, participants enrolled in the IPT-MBD arm attended >80% of therapy sessions. Parents and teens agreed that the frequency and duration of therapy were appropriate and were satisfied with IPT-MBD treatment. Clinical global impression scales for severity and improvement showed statistically greater improvement in the IPT-MBD group compared to TAU. Conclusions In this small pilot randomized trial, IPT-MBD was feasible and acceptable to parents and teens. There was significantly more improvement in the IPT-MBD group compared to TAU. IPT-MBD holds promise as a potentially effective psychosocial intervention for clinically impaired youth with DMDD and warrants further investigation in a larger randomized trial.

OBJECTIVE: Irritability is a common feature of many psychiatric disorders, including both externalizing and internalizing disorders. There is little research, however, examining associations between irritability and these symptom domains, particularly during the important developmental period of adolescence, characterized by sex differences in the prevalence of disorders. METHOD: We examined the cross-sectional associations between irritability, measured with the Affective Reactivity Index, and symptoms of externalizing and internalizing domains of psychopathology, measured with the Youth Self Report, in a volunteer community sample of 183 9- to-13-year-old (M=11.39, SD=1.07) boys and girls (37% White/Caucasian, 8% Asian, 11% Hispanic, 8% African American, 2% Native American, 2% Pacific Islander, 28% Other, and 3% not reported). A subset of the sample (n=112) provided data at a two-year follow-up, used to extend these associations. RESULTS: There were no sex differences in levels of irritability; however, the associations between irritability and symptom domains were moderated by sex. Specifically, in girls, irritability was associated equally with externalizing and internalizing symptoms. In contrast, in boys, irritability was associated more strongly with externalizing symptoms than with internalizing symptoms. Thus, across both sexes irritability was moderately associated with externalizing symptoms, but the association between irritability and internalizing symptoms was stronger in girls than in boys. At follow-up, sex moderated the association between baseline irritability and later externalizing and internalizing symptoms. CONCLUSIONS: These findings indicate that irritability is associated with both externalizing and internalizing symptoms in early adolescence, and that irritability is associated with internalizing symptoms more strongly in girls than in boys.

National Institute of Developmental Psychiatry for Children and Adolescents, Sao Paulo Sao Paulo Research Foundation] Brazilian National Council for Scientific and Technological Development Shire Eli Lilly Janssen Novartis Sao Paulo Research Foundation Wellcome Trust U.K. National Institutes of Health Research University College London Johnson Johnson Objective: Previous studies have implicated aberrant reward processing in the pathogenesis of adolescent depression. However, no study has used functional connectivity within a distributed reward network, assessed using resting-state functional MRI (fMRI), to predict the onset of depression in adolescents. This study used reward network-based functional connectivity at baseline to predict depressive disorder at follow-up in a community sample of adolescents. Method: A total of 637 children 6-12 years old underwent resting-state fMRI. Discovery and replication analyses tested intrinsic functional connectivity (iFC) among nodes of a putative reward network. Logistic regression tested whether striatal node strength, a measure of reward-related iFC, predicted onset of a depressive disorder at 3-year follow-up. Further analyses investigated the specificity of this prediction. Results: Increased left ventral striatum node strength predicted increased risk for future depressive disorder (odds ratio=1.54, 95% CI=1.09-2.18), even after excluding participants who had depressive disorders at baseline (odds ratio=1.52, 95% CI=1.05-2.20). Among 11 reward-network nodes, only the left ventral striatum significantly predicted depression. Striatal node strength did not predict other common adolescent psychopathology, such as anxiety, attention deficit hyperactivity disorder, and substance use. Conclusions: Aberrant ventral striatum functional connectivity specifically predicts future risk for depressive disorder. This finding further emphasizes the need to understand how brain reward networks contribute to youth depression. Univ Fed Sao Paulo, Dept Psychiat, Lab Interdisciplinar Neurociencias Clin, Sao Paulo, Brazil NIMH, Mood Brain & Dev Unit, Emot & Dev Branch, Bethesda, MD 20892 USA Univ Fed ABC, Ctr Math Comp & Cognit, Santo Andre, Brazil Univ Fed Rio Grande do Sul, Dept Psychiat, Hosp Clin Porto Alegre, Porto Alegre, RS, Brazil Univ Sao Paulo, Dept & Inst Psychiat, Sao Paulo, Brazil NIMH, Sect Dev & Affect Neurosci, Bethesda, MD 20892 USA NIMH, Sect Mood Dysregulat & Neurosci, Emot & Dev Branch, Bethesda, MD 20892 USA Kings Coll London, Inst Psychiat Psychol & Neurosci, Dept Psychosis Studies, London, England Univ Fed Sao Paulo, Dept Psychiat, Sao Paulo, Brazil Univ Fed Sao Paulo, Dept Psychiat, Lab Interdisciplinar Neurociencias Clin, Sao Paulo, Brazil Univ Fed Sao Paulo, Dept Psychiat, Sao Paulo, Brazil FAPESP: 2014/50917-0 FAPESP: 2013/08531-5 CNPq: 465550/2014-2 Web of Science

Understanding the neural processes tied to the adult outcome of childhood attention deficit hyperactivity disorder (ADHD) could guide novel interventions to improve its clinical course. It has been argued that normalization of prefrontal cortical activity drives remission from ADHD, while anomalies in subcortical processes are "fixed," present even in remission. Using multimodal neuroimaging of inhibitory processes, the authors tested these hypotheses in adults followed since childhood, contrasting remitted against persistent ADHD.Adult participants (persistent ADHD, N=35; remit-ted ADHD, N=47; never affected, N=99) were scanned with functional MRI (fMRI) (N=85), magnetoencephalography (N=33), or both (N=63) during a response inhibition task.In fMRI analyses, during inhibition, right caudate anomalies reflected a childhood ADHD history and were present even among those who remitted. By contrast, differences related to adult outcome emerged in cortical (right inferior frontal and inferior parietal/precuneus) and cerebellar regions. The persistent ADHD group showed under-activation, whereas the remitted ADHD group did not differ significantly from the never-affected group. Magnetoencephalography showed that the association between adult symptom severity and prefrontal neuronal activity was confined to the time window covering the act of inhibition (300 ms-350 ms). Group differences in cerebellar and parietal neuronal activity occurred during the time window of performance monitoring processes (500 ms-600 ms).By combining fMRI and magnetoencephalography, the location and time window of neuronal activity that underpins the adult outcome of ADHD was pinpointed. Thus, the cortico-cerebellar processes tied to the clinical course of ADHD are separated from the subcortical processes that are not.

Background By conceptualizing domains of behavior transdiagnostically, the National Institute of Mental Health Research Domain Criteria (NIMH RDoC) initiative facilitates new ways of studying psychiatric symptoms. In this study, latent profile analysis (LPA) was used to empirically derive classes or patterns of psychiatric symptoms in youth that transect traditional nosologic boundaries. Methods Data were drawn from 509 children and adolescents (ages 7 to 18 years; mean age = 12.9 years; 54% male) who were evaluated in the NIMH Emotion and Development Branch and were heterogeneous with respect to presenting diagnoses and symptoms. Youth and/or their parents completed measures of several core symptom dimensions: irritability, anxiety, depression, and attention deficit hyperactivity disorder (ADHD). LPA was used to parse response patterns into distinct classes, based on the levels of, and interrelations among, scores on the different measures. Results Five classes emerged: low levels of symptomatology (52% of sample); anxiety and mild depressive symptoms (17%); parent-reported irritability and ADHD (16%); irritability and mixed comorbid symptoms (10%); and high levels of irritability, anxiety, depression, and ADHD (5%). Importantly, these latent classes cut across informants and the clinical conditions for which youth were initially evaluated. Further, the classes characterized by irritability exhibited the poorest overall functioning. Limitations These data were cross-sectional. Examination of external validators, including neurobiological correlates and symptom course, is warranted. Conclusions Results inform our understanding of the structure of psychiatric symptoms in youth and suggest new ways to operationalize psychopathology and examine it in relation to neurobiology.

Perturbations in the prefrontal cortex (PFC), hippocampus, and amygdala are implicated in the development of anxiety disorders. However, most structural neuroimaging studies of patients with anxiety disorders utilize adult samples, and the few studies in youths examine small samples, primarily with volume-based measures. This study tested the hypothesis that cortical thickness of PFC regions and gray matter volume of the hippocampus and amygdala differ between pediatric anxiety disorder patients and healthy volunteers (HVs). High-resolution 3-Tesla T1-weighted MRI scans were acquired in 151 youths (75 anxious, 76 HV; ages 8–18). Analyses tested associations of brain structure with anxiety diagnosis and severity across both groups, as well as response to cognitive-behavioral therapy in a subset of 53 patients. Cortical thickness was evaluated both within an a priori PFC mask (small-volume corrected) and using an exploratory whole-brain-corrected (p

The current 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-years 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 between BI, AB, and anxiety.

Little is known regarding the neural connectivity and correlates during automatic, unconscious face emotion processing in individuals with bipolar disorder (BD). In this study, 14 adults with BD and 14 healthy volunteers (HV) underwent fMRI scanning while completing an affective priming task with unconsciously perceived and consciously perceived faces (angry, happy, neutral, blank oval). We found that, regardless of awareness level and emotion types, BD patients exhibited diminished functional connectivity between amygdala and ventromedial prefrontal cortex (vmPFC) compared to HV. This connectivity finding is present in the absence of activation differences in amygdala. In addition, in medial frontal gyrus, BD patients displayed greater activation while HV displayed less activation to angry and neutral faces compared to blank ovals. These results suggest that aberrant amygdala-vmPFC connectivity and neural dysfunction in areas implicated in appraisal and expression of emotions (medial frontal gyrus) may be the pathophysiological correlates of emotional processing in BD regardless of awareness level.

Background While translational theories link neurodevelopmental changes in threat learning to pathological anxiety, findings from studies in patients inconsistently support these theories. This inconsistency may reflect difficulties in studying large patient samples with wide age ranges using consistent methods. A dearth of imaging data in patients further limits translational advances. We address these gaps through a psychophysiology and structural brain imaging study in a large sample of patients across the lifespan. Methods A total of 351 participants (8–50 years of age; 209 female subjects; 195 healthy participants and 156 medication-free, treatment-seeking patients with anxiety) completed a differential threat conditioning and extinction paradigm that has been validated in pediatric and adult populations. Skin conductance response indexed psychophysiological response to conditioned (CS+, CS−) and unconditioned threat stimuli. Structural magnetic resonance imaging data were available for 250 participants. Analyses tested anxiety and age associations with psychophysiological response in addition to associations between psychophysiology and brain structure. Results Regardless of age, patients and healthy comparison subjects demonstrated comparable differential threat conditioning and extinction. The magnitude of skin conductance response to both conditioned stimulus types differentiated patients from comparison subjects and covaried with dorsal prefrontal cortical thickness; structure–response associations were moderated by anxiety and age in several regions. Unconditioned responding was unrelated to anxiety and brain structure. Conclusions Rather than impaired threat learning, pathological anxiety involves heightened skin conductance response to potential but not immediately present threats; this anxiety-related potentiation of anticipatory responding also relates to variation in brain structure. These findings inform theoretical considerations by highlighting anticipatory response to potential threat in anxiety.

The current study examined the link between temperamental reactivity in infancy and amygdala development in middle childhood. A sample (n = 291) of four-month-old infants was assessed for infant temperament, and two groups were identified: those exhibiting negative reactivity (n = 116) and those exhibiting positive reactivity (n = 106). At 10 and 12 years of age structural imaging was completed on a subset of these participants (n = 75). Results indicate that, between 10 and 12 years of age, left amygdala volume increased more slowly in those with negative compared to positive reactive temperament. These results provide novel evidence linking early temperament to distinct patterns of brain development over middle childhood.

Neuroimaging studies typically focus on either resting state or task-based fMRI data. Prior research has shown that similarity in functional connectivity between rest and cognitive tasks, interpreted as reconfiguration efficiency, is related to task performance and IQ. Here, we extend this approach from adults to children, and from cognitive tasks to a threat-based attention task. The goal of the current study was to examine whether similarity in functional connectivity during rest and an attention bias task relates to threat bias, IQ, anxiety symptoms, and social reticence. fMRI was measured during resting state and during the dot-probe task in 41 children (M = 13.44, SD = 0.70). Functional connectivity during rest and dot-probe was positively correlated, suggesting that functional hierarchies in the brain are stable. Similarity in functional connectivity between rest and the dot-probe task only related to threat bias (p(uncorr) < .03). This effect did not survive correction for multiple testing. Overall, children who allocate more attention towards threat also may possess greater reconfiguration efficiency in switching from intrinsic to threat-related attention states. Finally, functional connectivity correlated negatively across the two conditions of the dot-probe task. Opposing patterns of modulation of functional connectivity by threat-congruent and threat-incongruent trials may reflect task-specific network changes during two different attentional processes.

Objective: Irritability, which is strongly associated with impairment and negative outcomes, is a common reason for referral to mental health services but is a nosological and treatment challenge. A major issue is how irritability should be conceptualized. The authors used a developmental approach to test the hypothesis that there are several forms of irritability, including a “neurodevelopmental/ADHD-like” type, with onset in childhood, and a “depression/mood” type, with onset in adolescence. Methods: Data were analyzed from the Avon Longitudinal Study of Parents and Children, a prospective U.K. population-based cohort. Irritability trajectory classes were estimated for 7,924 individuals with data at multiple time points across childhood and adolescence (four possible time points from approximately ages 7 to 15). Psychiatric diagnoses were assessed at approximately ages 7 and 15. Psychiatric genetic risk was indexed by polygenic risk scores (PRSs) for attention deficit hyperactivity disorder (ADHD) and depression, derived using large genome-wide association study results. Results: Five irritability trajectory classes were identified: low (81.2%), decreasing (5.6%), increasing (5.5%), late-childhood limited (5.2%), and high-persistent (2.4%). The early-onset high-persistent trajectory was associated with male preponderance, childhood ADHD (odds ratio=108.64, 95% CI=57.45–204.41), and ADHD PRS (odds ratio=1.31, 95% CI=1.09–1.58). The adolescent-onset increasing trajectory was associated with female preponderance, adolescent depression (odds ratio=5.14, 95% CI=2.47–10.73), and depression PRS (odds ratio=1.20, 95% CI=1.05–1.38). Both the early-onset high-persistent and adolescent-onset increasing trajectory classes were associated with adolescent depression diagnosis and ADHD PRS. Conclusions: The developmental context of irritability may be important in its conceptualization: early-onset persistent irritability may be more neurodevelopmental/ADHD-like and later-onset irritability more depression/mood-like. These findings have implications for treatment as well as nosology.

BackgroundIrritability is an important dimension of psychopathology that spans multiple clinical diagnostic categories, yet its relationship to patterns of brain development remains sparsely explored. Here, we examined how trans-diagnostic symptoms of irritability relate to the development of structural brain networks.MethodsAll participants (n=144, 87 females) completed structural brain imaging with 3 Tesla MRI at two timepoints (mean age at follow-up: 20.9 years, mean inter-scan interval: 5.1 years). Irritability at follow-up was assessed using the Affective Reactivity Index, and cortical thickness was quantified using Advanced Normalization Tools software. Structural covariance networks were delineated using non-negative matrix factorization, a multivariate analysis technique. Both cross-sectional and longitudinal associations with irritability at follow-up were evaluated using generalized additive models with penalized splines. The False Discovery Rate (qResultsCross-sectional analysis of follow-up data revealed that 11 of the 24 covariance networks were associated with irritability, with higher levels of irritability being associated with thinner cortex. Longitudinal analyses further revealed that accelerated cortical thinning within 9 networks was related to irritability at follow-up. Effects were particularly prominent in brain regions implicated in emotion regulation, including the orbitofrontal, lateral temporal, and medial temporal cortex.ConclusionsCollectively, these findings suggest that irritability is associated with widespread cortical thickness reductions and accelerated cortical thinning, particularly within frontal and temporal cortex. Aberrant structural maturation of regions important for emotional regulation may in part underlie symptoms of irritability.

Wariness in early childhood manifests as shy, inhibited behavior in novel social situations and is associated with increased risk for developing social anxiety. In youth with childhood wariness, exposure to a potent social stressor, such as peer victimization, may potentiate brain-based sensitivity to unpredictable social contexts, thereby increasing risk for developing social anxiety. To test brain-based associations between early childhood wariness, self-reported peer victimization, and current social anxiety symptoms, we quantified neural responses to different social contexts in low- and high-victimized pre-adolescents with varying levels of early childhood wariness. Measures of early childhood wariness were obtained annually from ages 2-to-7-years. At age 11, participants were characterized as having low (N = 20) or high (N = 27) peer victimization. To index their neural responses to peer evaluation, participants completed an fMRI-based Virtual School paradigm (Jarcho et al. Developmental Cognitive Neuroscience, 13, 21–31, 2013a). In highly victimized, relative to low-victimized participants, wariness was differentially related to right amygdala response based on the valence and predictability of peer evaluation. More specifically, in highly victimized participants, wariness was associated with greater right amygdala response to unpredictably positive peer evaluation. Effects of wariness were not observed in participants who reported low levels of victimization. Moreover, in victimized participants, high wariness and right amygdala response to unpredictably positive peer evaluation was associated with more severe social anxiety symptoms. Results can be interpreted using a diathesis-stress model, which suggests that neural response to unexpectedly positive social feedback is a mechanism by which exposure to peer victimization potentiates the risk for developing social anxiety in individuals exhibiting high levels of early childhood wariness.

Background Little is known about genetic and environmental influences on the components of disruptive mood dysregulation disorder (DMDD), tonic irritability (i.e., irritable mood) and phasic irritability (i.e., temper outbursts). This study examined prevalence, stability, and heritability of tonic irritability, phasic irritability, and a DMDD proxy (pDMDD) based on DSM-5 criteria. Methods pDMDD was derived using data from clinical interviews of parents and their twins (N = 1,431 twin pairs), ages 8-17, participating in Waves 1 and 2 of the Virginia Twin Study of Adolescent Behavioral Development. Biometrical modeling was used to compare a common pathway model (CPM) and an independent pathway model (IPM), and heritability estimates were obtained for pDMDD using the symptoms of irritable mood (tonic irritability; DMDD Criterion D), intense temper outbursts (phasic irritability; DMDD Criterion A), and frequent temper outbursts (phasic irritability; DMDD Criterion C). Results Lifetime prevalence of pDMDD was 7.46%. The stability of DMDD symptoms and the pDMDD phenotype across approximately one year were moderate (.30-.69). A CPM was a better fit to the data than an IPM. Phasic irritability loaded strongly onto the pDMDD latent factor (.89-.96) whereas tonic irritability did not (.28). Genetic influences accounted for approximately 59% of the variance in the latent pDMDD phenotype, with the remaining 41% of the variance due to unique environmental effects. The heritability of tonic irritability (54%) was slightly lower than that of frequent and intense temper (components of phasic irritability; 61% and 63%, respectively). Conclusions Compared to tonic irritability, phasic irritability appears to be slightly more stable and heritable, as well as a stronger indicator of the latent factor. Furthermore, environmental experiences appear to play a substantial role in the development of irritability and DMDD, and researchers should seek to elucidate these mechanisms in future work.

While emotional dysregulation is a broad construct, the current paper adopts a narrow approach to facilitate translational neuroscience research on pediatric anxiety. The paper first presents data on an adapted version of the antisaccade task and then integrates these data into a research framework. Data on an adapted version of the antisaccade task were collected in 57 youth, including 35 seeking treatment for an anxiety disorder. Associations were examined between performance on the antisaccade task and (a) age, (b) performance on other cognitive-control tasks (i.e., the stop-signal delay and flanker tasks), and (c) level of anxiety symptoms. Better performance on the antisaccade task occurred in older relative to younger subjects and correlated with better performance on the flanker task. Across the 57 youth, higher levels of anxiety correlated with shorter latency for correct antisaccades. These data can be placed within a three-step framework for translational neuroscience research. In the first step, a narrow index of emotion dysregulation is targeted. In the second step, this narrow index is linked to other correlated indicators of the same underlying narrow latent construct. In the third and final step, associations are examined with clinical outcomes and response to treatment.

Highlights • Threat circuit function may develop differently in children with different temperamental profiles, such as high vs. low social reticence. • We relate individual differences in longitudinally assessed, observed socially reticent behavior to brain-physiology interactions during extinction recall. • Childhood social reticence predicts a distinct pattern of hemodynamic-autonomic covariation when recalling extinguished threat and safety cues. • Covariation patterns indicated that socially reticent youth had difficulty tracking safety as a function of stimulus resemblance to the safe stimulus., Social Reticence (SR) is a temperament construct identified in early childhood that is expressed as shy, anxiously avoidant behavior and, particularly when stable, robustly associated with risk for anxiety disorders. Threat circuit function may develop differently for children high on SR than low on SR. We compared brain function and behavior during extinction recall in a sample of 11-to-15-year-old children characterized in early childhood on a continuum of SR. 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. Whereas self-report and psychophysiological measures of differential conditioning, extinction, and extinction recall were largely similar across participants, SR-related differences in brain function emerged during extinction recall. Specifically, childhood SR was associated with a distinct pattern of hemodynamic-autonomic covariation in the brain when recalling extinguished threat and safety cues. SR and attention focus impacted associations between trial-by-trial variation in autonomic responding and in brain activation. These interactions occurred in three main brain areas: the anterior insular cortex (AIC), the anterior subdivision of the medial cingulate cortex (aMCC), and the dorsolateral prefrontal cortex (dlPFC). This pattern of SCR-BOLD coupling may reflect selective difficulty tracking safety in a temperamentally at-risk population.

Importance Anhedonia can present in children and predict detrimental clinical outcomes. Objective To map anhedonia in children onto changes in intrinsic large-scale connectivity and task-evoked activation and to probe the specificity of these changes in anhedonia against other clinical phenotypes (low mood, anxiety, and attention-deficit/hyperactivity disorder [ADHD]). Design, Setting, and Participants Functional magnetic resonance imaging (fMRI) data were from the first annual release of the Adolescent Brain Cognitive Development study, collected between September 2016 and September 2017 and analyzed between April and September 2018. Cross-sectional data of children aged 9 to 10 years from unreferred, community samples during rest (n = 2455) and during reward anticipation (n = 2566) and working memory (n = 2465) were analyzed. Main Outcomes and Measures Alterations in fMRI data during rest, reward anticipation, and working memory were examined, using both frequentist and Bayesian approaches. Functional MRI connectivity within large-scale networks, between networks, and between networks and subcortical regions were examined during rest. Functional MRI activation were examined during reward anticipation and working memory using the monetary incentive delayed and N-back tasks, respectively. Results Among 2455 children with adequate-quality resting-state fMRI data (mean [SD] age, 10.04 [0.62] years; 1187 girls [48.35%]), children with anhedonia (215 [8.76%]), compared with those without anhedonia (2222 [90.51%]), showed hypoconnectivity among various large-scale networks and subcortical regions, including within the arousal-related cingulo-opercular network (mean [SD] with anhedonia, 0.27 [0.08] vs without anhedonia, 0.29 [0.08];t2,435 = 3.14;P = .002; q[false discovery rate] = 0.07; ln[Bayes factor10] = 2.32). Such hypoconnectivity did not manifest among children with low mood (241 of 2455 [9.82%]), anxiety (93 of 2455 [3.79%]), or ADHD (397 of 2455 [16.17%]), suggesting specificity. Similarly, among 2566 children (mean [SD] age, 10.03 [0.62] years; 1257 girls [48.99%]) with high-quality task-evoked fMRI data, children with anhedonia (213 of 2566 [8.3%]) demonstrated hypoactivation during reward anticipation in various areas, including the dorsal striatum and areas of the cingulo-opercular network. This hypoactivity was not found among children with low mood (240 of 2566 [9.35%]), anxiety (83 of 2566 [3.23%]), or ADHD (430 of 2566 [16.76%]). Moreover, we also found context- and phenotype-specific double dissociations; while children with anhedonia showed altered activation during reward anticipation (but not working memory), those with ADHD showed altered activation during working memory (but not reward anticipation). Conclusions and Relevance Using the Adolescent Brain Cognitive Development study data set, phenotype-specific alterations were found in intrinsic large-scale connectivity and task-evoked activation in children with anhedonia. The hypoconnectivity at rest and hypoactivation during reward anticipation complementarily map anhedonia onto aberrations in neural-cognitive processes: lack of intrinsic arousal connectivity during rest and diminishment of extrinsic reward-arousal activity during reward anticipation. These findings help delineate the pathophysiological underpinnings of anhedonia in children.

Background Children with neurodevelopmental disorders are at increased risk of developing depression. Irritability predicts depression in the general population and is common in children with neurodevelopmental disorders. Thus, it is possible that irritability in children with neurodevelopmental disorders contributes to the link with later depression. This study aimed to (a) examine the association between childhood neurodevelopmental difficulties and adolescent depression and (b) test whether irritability explains this association. Methods Children with any neurodevelopmental difficulty at the age of 7–9 (n = 1,697) and a selected, comparison group without any neurodevelopmental difficulty (n = 3,177) were identified from a prospective, UK population‐based cohort, the Avon Longitudinal Study of Parents and Children. Neurodevelopmental difficulties were defined as a score in the bottom 5% of the sample on at least one measure of cognitive ability, communication, autism spectrum symptoms, attention‐deficit/hyperactivity symptoms, reading or motor coordination. The Development and Well‐Being Assessment measured parent‐reported child irritability at the age of 7, parent‐reported adolescent depression at the age of 10 and 13, and self‐reported depression at the age of 15. Depression measures were combined, deriving an outcome of major depressive disorder (MDD) in adolescence. Logistic regression examined the association between childhood neurodevelopmental difficulties and adolescent MDD, controlling for gender. Path analysis estimated the proportion of this association explained by irritability. Analyses were repeated for individual neurodevelopmental problems. Results Childhood neurodevelopmental difficulties were associated with adolescent MDD (OR = 2.11, 95% CI = 1.24, 3.60, p = .006). Childhood irritability statistically accounted for 42% of this association. On examining each neurodevelopmental difficulty separately, autistic, communication and ADHD problems were each associated with depression, with irritability explaining 29%–51% of these links. Conclusions Childhood irritability appears to be a key contributor to the link between childhood neurodevelopmental difficulties and adolescent MDD. High rates of irritability in children with autistic and ADHD difficulties may explain elevated rates of depression in the neurodevelopmental group.

BackgroundAnxiety 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.MethodsEighty-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.ResultsIn children with a history of high early-childhood BI, anxiety symptoms became, with age, morenegativelyassociated with right amygdala–left dorsolateral-PFC connectivity when attention was to be maintained on threat. In contrast, with age, low-BI children showed an increasinglypositiveanxiety–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.ConclusionsEarly-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.

Fear and anxiety are conceptualized as responses to acute or potential threat, respectively. Adult twin studies found substantial interplay between genetic and environmental factors influencing fear disorders (phobias) and anxiety disorders. Research in children, however, has largely examined these factors independently. Thus, there exists a substantial knowledge gap regarding the underlying etiologic structure of these closely-related constructs during development. Symptom counts for five fear (criticism, the unknown, death, animal, medical) and four anxiety (generalized, panic, separation, social) dimensions were obtained for 373 twin pairs ages 9-14. Multivariate twin modeling was performed to elucidate the genetic and environmental influences distributed amongst these dimensions. The best fitting model contained one genetic, two familial environmental, and two unique environmental factors shared between fear and anxiety symptoms plus dimension-specific genetic and unique environmental factors. Although several environmental factors were shared between fear and anxiety dimensions, one latent factor accounted for genetic influences across both domains. While adult studies find somewhat distinct etiological differences between anxiety and phobic disorders, the current results suggest that their relative genetic and environmental influences are not as clearly demarcated in children. These etiological distinctions are more nuanced, likely contributing to the highly diffuse symptom patterns seen during development.