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PURPOSE OF REVIEW: Chronic, severe irritability is a common presenting problem in children and adolescents. Disruptive mood dysregulation disorder (DMDD) was added to the DSM-5 in recognition of this public health need. Currently there are no well-established, evidence-based pharmacological or psychosocial treatments specifically for DMDD. Here, we focus on psychosocial interventions. In addition to reviewing published research, we present preliminary, open trial data on a novel exposure-based cognitive-behavioral therapy (CBT) targeting severe irritability, as is present in DMDD. RECENT FINDINGS: In the published literature, parent management training (PMT) comprises parent-based interventions designed to treat youth disruptive behavior. Child-based interventions for disruptive behavior include CBT focused on social cognition and problem-solving. Based on identified treatment gaps for severe irritability in children and adolescents, novel psychosocial interventions are being developed. We have developed a CBT for severe irritability that integrates exposure techniques, drawn from anxiety treatment, with selected PMT techniques. Data from an open pilot trial (N=10) suggest feasibility. SUMMARY: Promising psychosocial treatments are being developed for DMDD. Future directions include testing these new therapies against extant interventions. Increased research on the biological and psychological mechanisms mediating irritability will further bridge the treatment gap for youth and families.

The Journal’s 175th anniversary combined with recent advances in research provides an ideal opportunity to present a neurodevelopmental roadmap for understanding, preventing, and treating psychiatric disorders. Such a roadmap is particularly relevant for early childhood onset neurodevelopmental conditions, which emerge when experience-dependent neuroplasticity is at its peak. Employing a novel developmental specification approach, this review places recent neurodevelopmental research on early childhood disruptive behavior within the historical context of The Journal. We highlight irritability and callous behavior as two core exemplars of early disruptive behavior. Both phenotypes can be reliably differentiated from normative variation as early as the first years of life. Both link to discrete pathophysiology: irritability with disruptions in prefrontal regulation of emotion, and callous behavior with abnormal fear processing. Each phenotype also possesses clinical and predictive utility. Based on a nomologic net of evidence, we conclude that early disruptive behavior is neurodevelopmental in nature, and should be reclassified as an early childhood-onset neurodevelopmental condition in DSM 5. Rapid translation from neurodevelopmental discovery to clinical application has transformative potential for psychiatric approaches of the millennium.

Multiple psychiatric disorders are associated with difficulties in facial emotion recognition. However, generalized anxiety disorder may be associated with more accurate recognition of others’ emotional expressions, particularly expressions of happiness and fear, which index safety and threat. Children aged 9–14 from a community sample (N = 601) completed a facial emotion labeling task. Children’s symptoms of depressive and anxiety syndromes were assessed by self- and parent-report. Elevated symptoms of generalized anxiety disorder were associated with more accurate facial emotion recognition (β = 0.16, p = 0.007), specifically recognition of happiness (β = 0.17, p = 0.002) and fear (β = 0.15, p = 0.006). Elevated depressive symptoms were associated with less accurate facial emotion recognition (β = −0.12, p = 0.018), specifically happiness (β = −0.15, p = 0.002). Elevated symptoms of separation anxiety disorder were also associated with less accurate facial emotion recognition (β = −0.16, p = 0.003), specifically happiness (β = −0.15, p = 0.006) and fear (β = −0.15, p = 0.005), which highlights the importance of distinguishing between anxiety syndromes. Results held when adjusting for child age and sex. Evidence that symptoms of generalized anxiety disorder are associated with more accurate recognition of happiness and fear is consistent with theories of heightened social vigilance and support a transdiagnostic role of facial emotion recognition that may inform the psychosocial development of youth with anxiety and depressive symptoms.

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

Background Irritability is one of the most common reasons for referral to child and adolescent mental health services and is the main characteristic of the new diagnosis of disruptive mood dysregulation disorder (DMDD). However, the recognition and management of irritability presents a major challenge in clinical practice and may be partly responsible for the dramatic increase in antipsychotic prescribing in recent years. Methods In this review, we provide up-to-date information on the definition and mechanisms underlying irritability, and its assessment in clinical practice. We aim to discuss the latest research on DMDD, and the presence of severe irritability in the context of other disorders, as well as to recommend a treatment algorithm. Results Severe irritability is associated with aberrant reward processing and bias toward threatening stimuli. Several measures are available to easily assess irritability. The recent diagnosis of DMDD captures children whose main problem is severe irritability and differ from those with bipolar disorder in longitudinal outcomes, family history, and behavioral and neural correlates. Treatment of irritability might depend on the context it appears. Indirect evidence suggests that parent management training (PMT) and cognitive behavioral therapy (CBT) are the most supported psychological treatments for irritability. Conclusions Irritability, recognized as a mood problem rather than a purely behavioral manifestation, is a common condition for young people. Practitioners should not ignore irritability as it is associated with substantial morbidity and impairment. Although there are no trials with irritability as main outcome, clinicians can apply several existing pharmacological and psychological interventions for its treatment. Also, new promising approaches relying on pathophysiological findings, such as exposure-based cognitive behavioral therapy techniques and interpretation bias training (IBT), are being currently investigated.

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.

Although irritability is among the most common reasons that children and adolescents are brought for psychiatric care, there are few effective treatments. Developmentally sensitive pathophysiological models are needed to guide treatment development. In this review, the authors present a mechanistic model of irritability that integrates clinical and translational neuroscience research. Two complementary conceptualizations of pathological irritability are proposed: 1) aberrant emotional and behavioral responding to frustrative nonreward, mediated by reward-system dysfunction; and 2) aberrant approach responding to threat, mediated by threat-system dysfunction. The authors review the pathophysiological literature, including animal studies, as well as experimental psychology and clinical studies. Data suggest that, relative to healthy children, irritable children have deficient reward learning and elevated sensitivity to reward receipt and omission. These deficits are associated with dysfunction in the prefrontal cortex, striatum, and amygdala. Youths with irritability also show maladaptive orienting to, interpreting, and labeling of potential threats, associated with prefrontal cortical and amygdalar dysfunction. Abnormalities in reward and threat processing potentiate one another. Future work should test pathophysiological hypotheses and novel interventions targeting reward- and threat-related dysfunction to improve treatment for severe irritability in youths.

Background Internalizing disorders (IDs), consisting of the syndromes of anxiety and depression, are common, debilitating conditions often having onsets in adolescence. Scientists have developed dimensional self-report instruments that assess putative negative valence system (NVS) trait-like constructs as complimentary phenotypes to clinical symptoms. These include various measures that index temperamental predispositions to IDs and correlate with neural substrates of fear, anxiety, and affective regulation. This study sought to elucidate the overarching structure of putative NVS traits and their relationship to early manifestations of ID symptomatology. Methods The sample consisted of 768 juvenile twin subjects ages 9–13. Together with ID symptoms, extant validated instruments were chosen to assess a broad spectrum of NVS traits: anxiety sensitivity, irritability, fearfulness, behavioral activation and inhibition, and neuroticism and extraversion. Exploratory and confirmatory factor analyses (EFA/CFA) were used to investigate the latent structure of the associations among these different constructs and ID symptoms. Bifactor modeling in addition to standard correlated-factor analytic approaches were applied. Results Factor analyses produced a primary tripartite solution comprising anxiety/fear, dysphoria, and positive affect among all these measures. Competing DSM-like correlated factors and an RDoC-like NVS bifactor structure provided similar fit to these data. Conclusions Our findings support the conceptual organization of a tripartite latent internalizing domain in developing children. This structure includes both clinical symptoms and a variety of self-report dimensional traits currently in use by investigators. These various constructs are, therefore, most informatively investigated using an inclusive, integrated approach.

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

Irritability, defined as an increased propensity to exhibit increased anger relative to one's peers, is a common clinical problem in youth. Irritability can be conceptualized as aberrant responses to frustration (where frustration is the emotional response to blocked goal attainment) and/or aberrant 'approach' responses to threat. Irritable youth show hyper-reactivity to threat mediated by dysfunction in amygdala, medial prefrontal cortex (mPFC), anterior cingulate cortex (ACC), insula, striatum, and association cortex. Irritable youth also show abnormalities in reward learning, cognitive control, and responses to frustration. These abnormalities are mediated by circuitry that includes the inferior frontal gyrus (iFG), striatum, ACC, and parietal cortex. Effective treatments for irritability are lacking, but pathophysiological research could lead to more precisely targeted interventions.

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.

Early behaviors that differentiate later biomarkers for psychopathology can guide preventive efforts while also facilitating pathophysiological research. We tested whether error-related negativity (ERN) moderates the link between early behavior and later psychopathology in two early childhood phenotypes: behavioral inhibition and irritability. From ages 2 to 7 years, children (n = 291) were assessed longitudinally for behavioral inhibition (BI) and irritability. Behavioral inhibition was assessed via maternal report and behavioral responses to novelty. Childhood irritability was assessed using the Child Behavior Checklist. At age 12, an electroencephalogram (EEG) was recorded while children performed a flanker task to measure ERN, a neural indicator of error monitoring. Clinical assessments of anxiety and irritability were conducted using questionnaires (i.e., Screen for Child Anxiety Related Disorders and Affective Reactivity Index) and clinical interviews. Error monitoring interacted with early BI and early irritability to predict later psychopathology. Among children with high BI, an enhanced ERN predicted greater social anxiety at age 12. In contrast, children with high childhood irritability and blunted ERN predicted greater irritability at age 12. This converges with previous work and provides novel insight into the specificity of pathways associated with psychopathology.

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.

Pediatric irritability is prevalent and impairing, yet little is known about its pathophysiology and treatment. In this article, we build on our and others’ previous work to posit core mechanisms of irritability operating across the brain, behavior, and environment. Specifically, we propose proximal processes that surround the symptomatology of irritability and are potential targets for an exposure-based cognitive-behavioral therapy (CBT) for irritability that our group has developed. The heart of this model focuses on neurocognitive processes: youth’s encoding of nonreward and threat stimuli, which involves prediction error signaling in the brain, and cognitive control in the context of frustration. Alterations in these processes are theorized to be central to chronic, severe irritability. Environmental responses to youth’s symptom expression are also examined. Exposure-based CBT for irritability utilizes controlled, in vivo exposure to nonreward and threat stimuli with the aim to engage cognitive control and target top-down regulation of frustration. This intervention integrates selected parent management training (PMT) techniques to target symptom reinforcement processes. Continued pathophysiological and treatment studies of irritability will not only refine our emerging understanding of the phenotype, but also inform broader questions on the brain and behavioral mechanisms of CBT efficacy.

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.

Pediatric irritability is one of the most common reasons for mental health evaluation and treatment. Irritability is transdiagnostic; while it is the hallmark symptom of disruptive mood dysregulation disorder, a new diagnosis in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), it also appears in the diagnostic criteria for several mood, anxiety, and behavioral disorders and is a common correlate in others. The past 15 years have witnessed a rise in clinical neuroscience studies of pediatric irritability, resulting in significant advances in our understanding of its neural, genetic, psychophysiological, and behavioral correlates. These advances are detailed in the chapters in this volume. There is a particular focus on the implications of these findings for assessment and treatment of irritable youth, along with suggestions for further research.

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.

Few studies have used matched affective paradigms to compare humans and non-human primates. In monkeys with amygdala lesions and youth with anxiety disorders, we examined cross-species pupillary responses during a saccade-based, affective attentional capture task. Given evidence of enhanced amygdala function in anxiety, we hypothesized that opposite patterns would emerge in lesioned monkeys and anxious participants. A total of 53 unmedicated youths (27 anxious, 26 healthy) and 8 adult male rhesus monkeys (Macaca mulatta) completed matched behavioral paradigms. Four monkeys received bilateral excitotoxic amygdala lesions and four served as unoperated controls. Compared to healthy youth, anxious youth exhibited increased pupillary constriction in response to emotional and non-emotional distractors (F(1,48) = 6.28, P = 0.02, η2p = 0.12). Pupillary response was associated significantly with anxiety symptoms severity (F(1,48) = 5.59, P = 0.02, η2p = 0.10). As hypothesized, lesioned monkeys exhibited the opposite pattern i.e. decreased pupillary constriction in response to distractors, compared to unoperated control monkeys (F(1,32) = 24.22, P

BACKGROUND: Clinical researchers face challenges when trying to quantify diverse processes engaged during social interactions. We report results from two studies, each demonstrating the potential utility of tools for examining processes engaged during social interactions. METHOD: In the first study, youth (n = 57) used a smartphone‐based tool to rate mood and responses to social events. A subset (n = 20) completed the second, functional magnetic resonance imaging study. This second study related anxiety to error‐evoked brain responses in two social conditions—while being observed and when alone. We also combined these tools to bridge clinical, social‐contextual, and neural levels of measurement. RESULTS: Results from the first study showed an association between negatively-perceived social experiences and a range of negative emotions. In the second study there was a positive correlation during error monitoring between social‐anxiety severity and context‐specific activation of the pregenual anterior cingulate cortex. Finally, during imaging, the perceived quality of peer interactions as assessed using the smartphone‐based tool, interacted with social context to predict levels of activation in the hippocampus and superior frontal gyrus. CONCLUSIONS: By improving measurement, enhanced tools may provide new means for studying relationships among anxiety, brain function, and social interactions.

Children with anxiety disorders often present with other co-occurring symptom clusters, of which irritability is amongst the most highly co-occurring. Despite compelling clinical and pathophysiological evidence linking anxiety and irritability, little is known regarding the clinical presentation and associated impairment of children with both anxiety and irritability. In this study, our aims were to confirm the preponderance of irritability in clinically anxious children and compare clinically anxious children with irritability to those without irritability across sociodemographic, clinical, psychosocial, and family domains. Participants were 230 children with anxiety disorders (ages 6–14 years) and their mothers, and 91 healthy controls (ages 6–17 years) and their mothers. Of the clinically anxious children, 121 were anxious and irritable; 109 were anxious but not irritable. Irritability levels were significantly higher in the clinically anxious children compared with the healthy controls. Children with anxiety disorders and irritability presented with greater severity and impairment across clinical phenomenology, psychosocial, and family domains relative to anxious children without irritability. Regression analysis findings were convergent in that greater severity and impairment across these same domains predicted higher irritability levels in the children with anxiety disorders. Results support the meaningful distinction between anxious children with and without irritability. Implications of the findings are discussed particularly in regard to assessment and treatment and future research directions are delineated.

Background Irritability, a frequent complaint in children with psychiatric disorders, reflects increased predisposition to anger. Preliminary work in pediatric clinical samples links irritability to attention bias to threat, and the current study examines this association in a large population-based sample. Methods We studied 1,872 children (ages 6–14) using the Development and Well-Being Assessment (DAWBA), Childhood Behavior Checklist (CBCL), and dot-probe tasks. Irritability was defined using CBCL items that assessed temper tantrums and hot temper. The dot-probe task assessed attention biases for threat-related (angry face) stimuli. Multiple regression analysis was used to assess specificity of associations to irritability when adjusting for demographic variables and co-occurring psychiatric traits. Propensity score matching analysis was used to increase causal inference when matching for demographic variables and co-occurring psychiatric traits. Results Irritability was associated with increased attention bias toward threat-related cues. Multiple regression analysis suggests associations between irritability and threat bias are independent from demographic variables, anxiety, and externalizing traits (attention-deficit/hyperactivity, conduct, and headstrong/hurtful), but not from broad internalizing symptoms. Propensity score matching analysis indicated that this association was found for irritable versus nonirritable groups matched on demographic and co-occurring traits including internalizing symptoms. Conclusions Irritability in children is associated with biased attention toward threatening information. This finding, if replicated, warrants further investigation to examine the extent to which it contributes to chronic irritability and to explore possible treatment implications.

Bipolar disorder (BD) is a severe mental illness that can have high costs for youths (18 years old) and adults. Relative to healthy controls (HC), individuals with BD often show impaired attention, working memory, executive function, and cognitive flexibility (the ability to adapt to changing reward/punishment contingencies). In our study of youths and young adults with BD, we investigated 1) how cognitive flexibility varies developmentally in BD, and 2) whether it is independent of other executive function deficits associated with BD.We measured errors on a reversal-learning task, as well as spatial working memory and other executive function, among participants with BD (N=75) and HC (N=130), 7-27 years old. Regression analyses focused on the effects of diagnosis on reversal-learning errors, controlling for age, gender, IQ, spatial span, and executive function. Similar analyses examined non-reversal errors to rule out general task impairment.Participants with BD, regardless of age, gender, or cognitive ability, showed more errors than HC on the response reversal stages of the cognitive flexibility task. However, participants with BD did not show more errors on non-reversal stages, even when controlling for other variables.Study limitations include the cross-sectional, rather than longitudinal, design; inability to measure non-linear age effects; and inclusion of medicated participants and those with psychiatric comorbidity.Individuals with BD show a specific impairment in reversing a previously rewarded response, which persists across the transition from childhood to young adulthood. Tailored interventions targeting this deficit may be effective throughout this developmentally turbulent time.