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This project will examine the cross-sectional and longitudinal relations among parent-reported irritability, parent-reported ADHD symptoms, and a behavioral measure of inhibitory control in adolescents enrolled in The Adolescent Brain Cognitive Development℠ Study (ABCD Study®).

Irritability is a common, chronic, and impairing clinical phenotype in youth (Leibenluft, 2011; Stringaris et al., 2018). Severe irritability is codified in the DSM-5 diagnosis of disruptive mood dysregulation disorder (DMDD; American Psychiatric Association, 2013). Alterations in reward processing, including frustrative nonreward (i.e., omission of expected reward), are a proposed mechanism of pediatric irritability (Brotman et al., 2017; Leibenluft, 2017). However, only a handful of studies have directly examined reward processing in irritability (Adleman et al., 2011; Deveney, 2019; Deveney et al., 2013; Dougherty et al., 2018). Further, no published studies have examined reward prediction error (RPE; i.e., the difference between an expected outcome and a received outcome). Negative RPE (i.e., an outcome that is worse than expected) has particular relevance to frustrative nonreward (Kircanski et al., 2019). In this study, youth with DMDD and healthy volunteer (HV) youth completed a Monetary Incentive Delay (MID) task while undergoing functional magnetic resonance imaging (fMRI). In our primary analyses, we use this task to compare neural and behavioral aspects of RPE in DMDD vs. HV. In supplementary exploratory analyses, we examine neural correlates of anticipation and receipt of reward and loss in DMDD vs. HV, neural correlates of RPE along two core dimensions in DMDD (phasic and tonic irritability), and other neural and behavioral effects.

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 12-16years (M = 14.21years, SD = 1.44years), 62 of whom met criteria for ADHD. Approximately 18months 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.

Supplemental material, sj-pdf-1-cpx-10.1177_2167702621991805 for Deliberative Choice Strategies in Youths: Relevance to Transdiagnostic Anxiety Symptoms by Elise M. Cardinale, David Pagliaccio, Caroline Swetlitz, Hannah Grassie, Rany Abend, Vincent Costa, Bruno Averbeck, Melissa A. Brotman, Daniel S. Pine, Ellen Leibenluft and Katharina Kircanski in Clinical Psychological Science

OBJECTIVES: Frustration is associated with impaired attention, heightened arousal, and greater unhappiness in youths with bipolar disorder (BD) vs. healthy volunteers (HV). Little is known about functional connectivity in BD youths in response to frustration. This exploratory study compared BD youths and HV on attentional abilities, self-reported affect, and functional connectivity during a frustrating attentional task. METHODS: 20 BD (M(age)=15.86) and 20 HV (M(age)=15.55) youths completed a frustrating attention paradigm while undergoing functional magnetic resonance imaging (fMRI) scanning. Frustration was induced by providing participants with rigged feedback. We examined functional connectivity group differences using the inferior frontal gyrus (IFG) and amygdala as seeds. We explored task performance (accuracy, reaction time), self-reported frustration and unhappiness, and correlations between these variables and depressive and manic symptoms. RESULTS: BD youths, relative to HV, exhibited increased functional connectivity between IFG and ventromedial prefrontal cortex (vmPFC) during feedback processing and between IFG and parahippocampal gyrus (PHG)/periaqueductal gray (PAG) during attention orienting following frustration. BD vs. HV youths showed decreased connectivity between the amygdala and cerebellum during attention orienting following frustration. Across groups, higher depressive symptoms were associated with greater self-reported unhappiness under frustration. In BD, higher manic symptoms were associated with poorer accuracy under frustration. CONCLUSIONS: Increased IFG-vmPFC connectivity in BD during processing of non-frustrating and frustrating feedback may reflect heightened sensitivity to positively and negatively valenced stimuli. Elevated IFG-PAG/PHG connectivity in BD following frustration may suggest greater recruitment of attention network to regulate arousal and maintain goal-directed behavior.

The ENIGMA group on Generalized Anxiety Disorder (ENIGMA-Anxiety/GAD) is part of a broader effort to investigate anxiety disorders using imaging and genetic data across multiple sites worldwide. The group is actively conducting a mega-analysis of a large number of brain structural scans. In this process, the group was confronted with many methodological challenges related to study planning and implementation, between-country transfer of subject-level data, quality control of a considerable amount of imaging data, and choices related to statistical methods and efficient use of resources. This report summarizes the background information and rationale for the various methodological decisions, as well as the approach taken to implement them. The goal is to document the approach and help guide other research groups working with large brain imaging data sets as they develop their own analytic pipelines for mega-analyses. This report summarizes the background information and rationale for the various methodological decisions made by the ENIGMA-GAD group. The aim of this work is to help guide other research groups working with large brain imaging data sets

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 (1) examine the association between childhood neurodevelopmental difficulties and adolescent depression and (2) test whether irritability explains this association.Methods: Children with any neurodevelopmental difficulty at age 7-9 (n=1697) and a selected, comparison group without any neurodevelopmental difficulty (n=3177) 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 co-ordination. The Development and Well Being Assessment measured parent-reported child irritability at age 7, parent-reported adolescent depression at ages 10 and 13, and self-reported depression at age 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=0.006). 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.

Background Irritability and the new DSM-5 diagnostic category of Disruptive Mood Dysregulation Disorder (DMDD) have been conceptualised as related to mood disorder. Irritability is common in Attention Deficit Hyperactivity Disorder (ADHD) but little is known about its association with depression risk in this group. This study aims to establish levels of irritability and prevalence of DMDD in a clinical sample of children with ADHD, and examine their association with anxiety, depression and family history of depression. Methods The sample consisted of 696 children (mean age 10.9 years) with a diagnosis of ADHD, recruited from UK child psychiatry and paediatric clinics. Parents completed the Child and Adolescent Psychiatric Assessment, a semi-structured diagnostic interview, about their child. This was used to establish prevalence of DMDD, anxiety disorder and depressive disorder, as well as obtain symptom scores for irritability, anxiety and depression. Questionnaires assessed current parental depression, and family history of depression. Result Irritability was common, with 91% endorsing at least one irritable symptom. 3-month DMDD prevalence was 31%. Children with higher levels of irritability or DMDD were more likely to have comorbid symptoms of anxiety, depression and a family history of depression. Limitations Results are based on a clinical sample, so may not be generalizable to children with ADHD in the general population. Conclusions Irritability and DMDD were common, and were associated with markers of depression liability. Longitudinal studies are needed to examine the association between irritability and depression in youth with ADHD as they get older.

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.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.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.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.

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

This study examines the extent to which children's positive attributes are distinct from psychopathology. We also investigate whether positive attributes change or "buffer" the impact of low intelligence and high psychopathology on negative educational outcomes.METHOD:In a community sample of 2,240 children (6-14 years of age), we investigated associations among positive attributes, psychopathology, intelligence, and negative educational outcomes. Negative educational outcomes were operationalized as learning problems and poor academic performance. We tested the discriminant validity of psychopathology versus positive attributes using confirmatory factor analysis (CFA) and propensity score matching analysis (PSM), and used generalized estimating equations (GEE) models to test main effects and interactions among predictors of educational outcomes.RESULTS:According to both CFA and PSM, positive attributes and psychiatric symptoms were distinct constructs. Positive attributes were associated with lower levels of negative educational outcomes, independent of intelligence and psychopathology. Positive attributes buffer the negative effects of lower intelligence on learning problems, and higher psychopathology on poor academic performance.CONCLUSION:Children's positive attributes are associated with lower levels of negative school outcomes. Positive attributes act both independently and by modifying the negative effects of low intelligence and high psychiatric symptoms on educational outcomes. Subsequent research should test interventions designed to foster the development of positive attributes in children at high risk for educational problems.

BackgroundIrritability in people with autism spectrum disorders (ASD) is common and impairing, yet its mechanisms remain understudied. We investigated symptom reporting and mechanisms of irritability in ASD, focusing on the relation between irritability and physiological stress responses.MethodsForty-seven unmedicated boys with high-functioning ASD (hfASD) and 23 typically developing boys aged 10–16 years completed a psychosocial stress test. Changes in cortisol, heart rate and heart rate variability throughout the test were recorded. Self- and parent-reported measures of irritability were obtained. Irritability symptom reporting in the hfASD group was compared to two groups of boys without ASD: highly irritable boys (severe mood dysregulation, SMD; n = 40) and healthy-control boys (HC; n = 30).ResultsBoys with hfASD scored significantly higher on irritability than HC boys, and they reported a pattern of irritability symptoms closely resembling that of boys with SMD. The internal consistency of irritability in hfASD was high by parent- and self-report. Although boys with hfASD showed significant stress-induced changes in cortisol and heart rate, those who rated themselves as highly irritable had lower cortisol levels throughout the test compared to those low on irritability. Participants rated as highly irritable by their parents showed blunted cortisol and heart rate responses to stress. The effects of irritability on heart rate, but not cortisol, were accounted for by trait anxiety.ConclusionsIrritability can be measured reliably in hfASD and is associated with distinct biological responses to stress.

BackgroundBipolar disorder (BD) is highly familial, but studies have yet to examine preschoolers at risk for BD using standardized, developmentally appropriate clinical assessment tools. We used such methods to test whether preschoolers at familial risk for BD have more observed difficulty modulating emotions and behaviors than do low-risk preschoolers. Identification of emotional and behavioral difficulties in at-risk preschoolers is crucial for developing new approaches for early intervention and prevention of BD.MethodsUsing the standardized disruptive behavior diagnostic observation schedule (DB-DOS) protocol for preschoolers, we compared 23 preschoolers (M(age): 4.53 ± 0.73 years; 18 males) with a first-degree relative with BD to 21 preschoolers (M(age): 4.65 ± 0.84 years; 11 males) without a family history of BD. We characterized psychopathology in this sample using the Preschool Aged Psychiatric Assessment and behavioral and emotional problems using the Child Behavior Checklist.ResultsHigh-risk preschoolers demonstrated significantly more intense, pervasive, and clinically concerning problems in anger modulation and behavior dysregulation on the DB-DOS than the low-risk group. High-risk relative to low-risk preschoolers, were also more likely to have maternal-reported anxiety and oppositional defiant disorders and internalizing and externalizing problems.ConclusionsClinically concerning problems in anger modulation and behavior regulation, measured during standardized laboratory observation, differentiate preschoolers at high familial risk for BD from those at low risk. Investigation in a large longitudinal sample is critical for replication and for determining whether these observed behavioral differences can be reliably used as prodromal indicators of mood disorders.

Increased intrasubject variability in response time (ISVRT) is evident in healthy preschoolers at familial risk for bipolar disorder, suggesting it may be an endophenotype.

Background: Our objective was to compare self- and parent-reported irritability in youths with anxiety disorders, healthy youths, and those with mood disorders characterized by irritability. Irritability is a common but relatively understudied psychiatric symptom in child and adolescent anxiety disorders. In anxious youths, little is known about the severity of irritability, its impact on functioning, or the effect of informant source on reports of irritability. Method: We compared parent- and self-report forms of the Affective Reactivity Index (ARI), a validated measure of irritability, in youths ages 8-17 years with no psychopathology (healthy comparison, HC; n = 38), anxiety disorders (ANX; n = 42), bipolar disorder (BD; n = 35), or severe mood disregulation (SMD; n = 61;a phenotype characterised by chronic, severely impairing irritability). Results: Irritability was significantly higher in ANX than HC youths by both parent and self-report (Partial η2 = 0.24 and 0.22 respectively, P’s Discussion: By both parent and self-report, youths with anxiety disorders exhibit significantly more irritability and associated impairment than healthy subjects. Self-reported irritability in youths with anxiety disorders is comparable to that observed in youths with severe mood disorders, although parental reports of irritability differ among the disorders. Future research should examine the pathophysiology of anxiety-associated irritability, as well as its prognostic and treatment implications.

We used a dot-probe paradigm to examine attention bias toward threat (i.e., angry) and happy face stimuli in severe mood dysregulation (SMD) versus healthy comparison (HC) youth. The tendency to allocate attention to threat is well established in anxiety and other disorders of negative affect. SMD is characterized by the negative affect of irritability, and longitudinal studies suggest childhood irritability predicts adult anxiety and depression. Therefore, it is important to study pathophysiologic connections between irritability and anxiety disorders.SMD patients (N = 74) and HC youth (N = 42) completed a visual probe paradigm to assess attention bias to emotional faces. Diagnostic interviews were conducted and measures of irritability and anxiety were obtained in patients.SMD youth differed from HC youth in having a bias toward threatening faces (P.01). Threat bias was positively correlated with the severity of the SMD syndrome and depressive symptoms; degree of threat bias did not differ between SMD youth with and without co-occurring anxiety disorders or depression. SMD and HC youth did not differ in bias toward or away from happy faces.SMD youth demonstrate an attention bias toward threat, with greater threat bias associated with higher levels of SMD symptom severity. Our findings suggest that irritability may share a pathophysiological link with anxiety and depressive disorders. This finding suggests the value of exploring further whether attention bias modification treatments that are effective for anxiety are also helpful in the treatment of irritability.

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

There is debate as to whether chronic irritability (operationalized as severe mood dysregulation, SMD) is a developmental form of bipolar disorder (BD). Although structural brain abnormalities in BD have been demonstrated, no study compares neuroanatomy among SMD, BD, and healthy volunteers (HV) either cross-sectionally or over time. Furthermore, the developmental trajectories of structural abnormalities in BD or SMD are unknown. This study provides such data in BD, SMD, and HV.An optimized, modulated voxel-based morphometry (VBM) analysis was conducted on structural MRI scans from 201 children (78 SMD, 55 BD, and 68 HV). In addition, 92 children (31 SMD, 34 BD, and 27 HV) were rescanned after 2 years (mean interval 1.99 ± 0.94 years), to compare time-related changes among the three groups.Cross-sectionally, the groups differed in gray matter (GM) volume in presupplementary motor area (pre-SMA), dorsolateral prefrontal cortex (DLPFC), insula, and globus pallidus. The cortical differences were driven mainly by increased GM volume in HV compared with BD and SMD. In globus pallidus, there was increased GM in BD compared with HV and SMD. Longitudinally, group-by-time interactions were evident in two clusters in the superior/inferior parietal lobule (R SPL/IPL) and in the precuneus. In both clusters, the interactions were driven by an abnormal increase in volume in BD.Cross-sectionally, both BD and SMD are associated with structural abnormalities in frontal cortex, insula, and basal ganglia. Although some of these deficits overlap (insula and DLPFC), others differentiate SMD and BD (pre-SMA and globus pallidus). Abnormal developmental trajectories in lateral parietal cortex and precuneus are present in, and unique to, BD. Because of the high proportion of co-occurring ADHD in the SMD subjects, we could not separate effects of ADHD from those of SMD, and future research including a nonirritable ADHD group must address this issue.

Research on attention provides a promising framework for studying anxiety pathophysiology and treatment. The study of attention biases appears particularly pertinent to developmental research, as attention affects learning and has down-stream effects on behavior. This review summarizes recent findings about attention orienting in anxiety, drawing on findings in recent developmental psychopathology and affective neuroscience research. These findings generate specific insights about both development and therapeutics. The review goes beyond a traditional focus on biased processing of threats and considers biased processing of rewards. Building on this work, we then turn to the treatment of pediatric anxiety, where manipulation of attention to threat and/or reward may serve a therapeutic role as a component of Attention Bias Modification Therapy.

Attention biases toward threat are often detected in individuals with anxiety disorders. Threat biases can be measured experimentally through dot-probe paradigms, in which individuals detect a probe following a stimulus pair including a threat. On these tasks, individuals with anxiety tend to detect probes that occur in a location previously occupied by a threat (i.e., congruent) faster than when opposite threats (i.e., incongruent). In pediatric anxiety disorders, dot-probe paradigms detect abnormal attention biases toward threat and abnormal ventrolateral prefrontal cortex (vlPFC) function. However, it remains unclear if this aberrant vlPFC activation occurs while subjects process threats (e.g., angry faces) or, alternatively, while they process and respond to probes. This magnetoencephalography (MEG) study was designed to answer this question. Adolescents with either generalized anxiety disorder (GAD, n = 17) or no psychiatric diagnosis (n = 25) performed a dot-probe task involving angry and neutral faces while MEG data were collected. Synthetic Aperture Magnetometry (SAM) beamformer technique was used to determine whether there were group differences in power ratios while subjects processed threats (i.e., angry vs. neutral faces) or when subjects responded to incongruent versus. congruent probes. Group differences in vlPFC activation during the response period emerged with a 1-30 Hz frequency band. No group differences in vlPFC activation were detected in response to angry-face cues. In the dot-probe task, anxiety-related perturbations in vlPFC activation reflect abnormal attention control when responding to behaviorally relevant probes, but not to angry faces. Given that motor responses to these probes are used to calculate threat bias, this study provides insight into the pathophysiology reflected in this commonly used marker of anxiety. In addition, this finding may inform the development of novel anxiety-disorder treatments targeting the vlPFC to enhance attention control to task-relevant demands.

Accurate identification of nonverbal emotional cues is essential to successful social interactions, yet most research is limited to emotional face expression labeling. Little research focuses on the processing of emotional prosody, or tone of verbal speech, in clinical populations.Using the Diagnostic Analysis of Nonverbal Accuracy, the current study examined whether youths with pediatric-onset bipolar disorder (BD) and/or those with chronic and severe irritability (i.e. the severe mood dysregulation phenotype) are impaired in their ability to identify the emotional prosody of a spoken sentence with neutral content.Youths with severe mood dysregulation (n = 67) performed more poorly than healthy comparison children (n = 57), even when the sample was limited to unmedicated patients. Medicated BD youths (n = 52) exhibited impairment relative to healthy comparison children. No interactions between group and emotion were observed, suggesting that emotional prosody labeling problems may represent a general deficit in chronically irritable youths and in medicated youths with BD.In concert with previously documented facial emotion labeling deficits, difficulties ascertaining the correct emotional tone of a spoken sentence may contribute to emotion dysregulation in chronically irritable children, and possibly also in youths with BD.

With the emergence of new technologies, there has been an explosion of basic and clinical research on the affective and cognitive neuroscience of face processing and emotion perception. Adult emotional face stimuli are commonly used in these studies. For developmental research, there is a need for a validated set of child emotional faces. This paper describes the development of the National Institute of Mental Health Child Emotional Faces Picture Set (NIMH-ChEFS), a relatively large stimulus set with high quality, color images of the emotional faces of children. The set includes 482 photographs of fearful, angry, happy, sad and neutral child faces with two gaze conditions: direct and averted gaze. In this paper we describe the development of the NIMH-ChEFS and data on the set's validity based on ratings by 20 healthy adult raters. Agreement between the a priori emotion designation and the raters' labels was high and comparable with values reported for commonly used adult picture sets. Intensity, representativeness, and composite "goodness" ratings are also presented to guide researchers in their choice of specific stimuli for their studies. These data should give researchers confidence in the NIMH-ChEFS's validity for use in affective and social neuroscience research.

Data documenting the functional impairment associated with the diagnosis of bipolar disorder (BD) in children and adolescents highlight the need for greater understanding of its pathophysiology. Toward that end, we demonstrated previously that BD youth have behavioral deficits on reversal learning tasks. On such tasks, participants must first acquire a stimulus/response relationship through trial-and-error learning, and then discern when the stimulus/reward relationship reverses. Here, we use event-related functional magnetic resonance imaging (fMRI) to elucidate neural correlates of reversal learning deficits in euthymic BD youth compared to typically developing controls. We compared euthymic pediatric BD participants (n = 16) versus age-, sex-, and IQ-matched controls (n = 16). Our main outcome measure was blood oxygen level-dependent (BOLD) signal measured with fMRI during an event-related probabilistic reversal task.Pediatric BD participants had significantly greater neural activity than controls in fronto-parietal regions during the reversal phase, particularly in response to punished reversal errors (p0.05 corrected for multiple comparisons).Our current study suggests that during reversal learning, BD youths inefficiently recruit regions associated with processing response conflict and implementing alternative responses, including subdivisions of the frontal cortex and the parietal cortex. Such deficits are present in euthymic BD youth. Further work is necessary to evaluate the specificity of such alterations.

Background: Little is known about short-duration episodes of mania-like symptoms in youth. Here we determine the prevalence, morbid associations, and contribution to social impairment of a phenotype characterised by episodes during which symptom and impairment criteria for mania are met, but DSM-IV duration criteria are not (bipolar not otherwise specified; BP-NOS).Methods: A cross-sectional national survey of a sample (N = 5,326) of 8-19-year-olds from the general population using information from parents and youth. Outcome measures were prevalence rates and morbid associations assessed by the Developmental and Well-Being Assessment, and social impairment assessed by the impact scale of the Strengths and Difficulties Questionnaire.Results: While only seven individuals (.1%) met definite or probable DSM-IV criteria for BPI or BPII, the prevalence of BP-NOS was 10-fold higher, 1.1% by parent report and 1.5% by youth report. Parent-youth agreement was very low: kappa = .02, p > .05 for BP-NOS. Prevalence and episode duration for BP-NOS did not vary by age. BP-NOS showed strong associations with externalising disorders. After adjusting for a dimensional measure of general psychopathology, self-reported (but not parent-reported) BP-NOS remained associated with overall social impairment.Conclusions: BP meeting full DSM-IV criteria is rare in youth. BP-NOS, defined by episodes shorter than those required by DSM-IV, but during which DSM-IV symptom and impairment criteria are met, is commoner and may be associated with social impairment that is beyond what can be accounted for by other psychopathology. These findings support the importance of research into these short episodes during which manic symptoms are met in youth but they also call into question the extent to which BP-NOS in youth is a variant of DSM-IV BP - superficially similar symptoms may not necessarily imply deeper similarities in aetiology or treatment response.

Recurrent microdeletions and microduplications of a 600-kb genomic region of chromosome 16p11.2 have been implicated in childhood-onset developmental disorders. We report the association of 16p11.2 microduplications with schizophrenia in two large cohorts. The microduplication was detected in 12/1,906 (0.63%) cases and 1/3,971 (0.03%) controls (P = 1.2 x 10(-5), OR = 25.8) from the initial cohort, and in 9/2,645 (0.34%) cases and 1/2,420 (0.04%) controls (P = 0.022, OR = 8.3) of the replication cohort. The 16p11.2 microduplication was associated with a 14.5-fold increased risk of schizophrenia (95% CI (3.3, 62)) in the combined sample. A meta-analysis of datasets for multiple psychiatric disorders showed a significant association of the microduplication with schizophrenia (P = 4.8 x 10(-7)), bipolar disorder (P = 0.017) and autism (P = 1.9 x 10(-7)). In contrast, the reciprocal microdeletion was associated only with autism and developmental disorders (P = 2.3 x 10(-13)). Head circumference was larger in patients with the microdeletion than in patients with the microduplication (P = 0.0007).

Little is known about short-duration episodes of mania-like symptoms in youth. Here we determine the prevalence, morbid associations, and contribution to social impairment of a phenotype characterised by episodes during which symptom and impairment criteria for mania are met, but DSM-IV duration criteria are not (bipolar not otherwise specified; BP-NOS).A cross-sectional national survey of a sample (N = 5,326) of 8-19-year-olds from the general population using information from parents and youth. Outcome measures were prevalence rates and morbid associations assessed by the Developmental and Well-Being Assessment, and social impairment assessed by the impact scale of the Strengths and Difficulties Questionnaire.While only seven individuals (.1%) met definite or probable DSM-IV criteria for BPI or BPII, the prevalence of BP-NOS was 10-fold higher, 1.1% by parent report and 1.5% by youth report. Parent-youth agreement was very low: kappa = .02, p.05 for BP-NOS. Prevalence and episode duration for BP-NOS did not vary by age. BP-NOS showed strong associations with externalising disorders. After adjusting for a dimensional measure of general psychopathology, self-reported (but not parent-reported) BP-NOS remained associated with overall social impairment.BP meeting full DSM-IV criteria is rare in youth. BP-NOS, defined by episodes shorter than those required by DSM-IV, but during which DSM-IV symptom and impairment criteria are met, is commoner and may be associated with social impairment that is beyond what can be accounted for by other psychopathology. These findings support the importance of research into these short episodes during which manic symptoms are met in youth but they also call into question the extent to which BP-NOS in youth is a variant of DSM-IV BP - superficially similar symptoms may not necessarily imply deeper similarities in aetiology or treatment response.

OBJECTIVE: While adolescent anxiety disorders represent prevalent, debilitating conditions, few studies have explored their brain physiology. Using event-related functional magnetic resonance imaging (fMRI) and a behavioral measure of attention to angry faces, the authors evaluated differences in response between healthy adolescents and adolescents with generalized anxiety disorder.METHOD: In the primary trials of interest, 18 adolescents with generalized anxiety disorder and 15 comparison subjects of equivalent age/gender/IQ viewed angry/neutral face pairs during fMRI acquisition. Following the presentation of each face pair, subjects pressed a button to indicate whether a subsequent asterisk appeared on the same (congruent) or opposite (incongruent) side as the angry face. Reaction time differences between congruent and incongruent face trials provided a measure of attention bias to angry faces.RESULTS: Relative to the comparison subjects, patients with generalized anxiety disorder manifested greater right ventrolateral prefrontal cortex activation to trials containing angry faces. Patients with generalized anxiety disorder also showed greater attention bias away from angry faces. Ventrolateral prefrontal cortex activation differences remained evident when differences in attention bias were covaried. Finally, in an examination among patients of the association between degree of anxiety and brain activation, the authors found that as ventrolateral prefrontal cortex activation increased, severity of anxiety symptoms diminished.CONCLUSIONS: Adolescents with generalized anxiety disorder show greater right ventrolateral prefrontal cortex activation and attentional bias away from angry faces than healthy adolescents. Among patients, increased ventrolateral prefrontal cortex activation is associated with less severe anxiety, suggesting that this activation may serve as a compensatory response.

ObjectiveResearch and clinical interest in irritability have been on the rise in recent years. Yet several questions remain about the status of irritability in psychiatry, including whether irritability can be differentiated from other symptoms, whether it forms a distinct disorder, and whether it is a meaningful predictor of clinical outcomes. In this paper we try to answer these questions by reviewing the evidence on how reliably irritability can be measured and its validity.MethodWe combine a narrative and systematic review and meta-analysis of studies. For the systematic review and meta-analysis, we searched studies in Pubmed and Web of Science based on preselected criteria (i.e., irritability as a predictor of future psychiatric outcomes). One hundred sixty-three papers were reviewed, and 24 were included.ResultsWe find that irritability forms a distinct dimension with substantial stability across time and that it is specifically associated with depression and anxiety in longitudinal studies. Evidence from genetic studies reveals that irritability is moderately heritable, and its overlap with depression is explained mainly by genetic factors. Behavioral and neuroimaging studies find that youth with persistent irritability show altered activations in amygdala, striatum, and frontal regions compared with age-matched healthy volunteers. Most knowledge about the treatment of irritability is based on effects of treatment on related conditions or through post hoc analyses of trial data.ConclusionWe identify a number of research priorities including innovative experimental designs and priorities for treatment studies and conclude with recommendations for the assessment of irritability for researchers and clinicians.