Evaluating the development and well-being assessment (DAWBA) in pediatric anxiety and depression.

Enhancing screening practices and developing scalable diagnostic tools are imperative in response to the increasing prevalence of youth mental health challenges. Structured lay psychiatric interviews have emerged as one such promising tool. However, there remains limited research evaluating structured psychiatric interviews, specifically their characterization of internalizing disorders in treatment-seeking youth. This study evaluates the relationship between the Development and Well-Being Assessment (DAWBA), a structured psychiatric interview, and established measures of pediatric anxiety and depression, including the Screen for Child Anxiety Related Disorders (SCARED), the Pediatric Anxiety Rating Scale (PARS), and the Mood and Feelings Questionnaire (MFQ). The study comprised two independent clinical samples of treatment-seeking youth: sample one included 55 youth with anxiety and 29 healthy volunteers (HV), while sample two included 127 youth with Major Depressive Disorder and 73 HVs. We examined the association between the DAWBA band scores, indicating predicted risk for diagnosis, the SCARED and PARS (sample one), and the MFQ (sample two). An exploratory analysis was conducted in a subset of participants to test whether DAWBA band scores predicted the change in anxiety symptoms (SCARED, PARS) across a 12-week course of cognitive behavioral therapy. The results revealed that the DAWBA significantly predicted the SCARED, PARS and MFQ measures at baseline; however, it did not predict changes in anxiety symptoms across treatment. These findings suggest that the DAWBA may be a helpful screening tool for indexing anxiety and depression in treatment-seeking youth but is not especially predictive of longitudinal trajectories in symptomatology across psychotherapy.

Mood and Behaviors of Adolescents With Depression in a Longitudinal Study Before and During the COVID-19 Pandemic.

OBJECTIVE: To investigate whether, compared to pre-pandemic levels, depressive and anxiety symptoms in adolescents with depression increased during the pandemic. METHOD: We used data from National Institute of Mental Health Characterization and Treatment of Depression (NIMH CAT-D) cohort, a longitudinal case-control study that started pre-pandemic. Most of the participants are from the states of Maryland and Virginia in the United States. We compared depressive symptoms (1,820 measurements; 519 measurements pre-pandemic and 1,302 during the pandemic) and anxiety symptoms (1,800 measurements; 508 measurements pre-pandemic and 1,292 ratings during the pandemic) of 166 adolescents (109 girls, 96 adolescents with depression) before and during the pandemic. Data were collected during yearly clinical visits, interim 4-month follow-up visits, inpatient stays, and weekly outpatient sessions, with additional data collection during the pandemic. Pre-pandemic, healthy volunteers (HVs) had a median of 1 depressive and anxiety rating (range, 1-3), and adolescents with depression had a median of 2 ratings (anxiety rating range, 1-25; depressive rating range, 1-26). During the pandemic, HVs had a median of 8 anxiety ratings and 9 depressive ratings (range, 1-13), and adolescents with depression had a median of 7 anxiety and depressive ratings (range, 1-29). We also analyzed adolescent- and parent-reported behaviors in the CoRonavIruS Health Impact Survey (CRISIS), totaling 920 self-reported measures for 164 adolescents (112 girls, 92 adolescents with depression). HVs had a median of 7 surveys (range, 1-8), and adolescents with depression had a median of 5 surveys (range, 1-8). RESULTS: Pre-pandemic, adolescents with depression had a mean depressive score of 11.16 (95% CI = 10.10, 12.22) and HVs had a mean depressive score of 1.76 (95% CI = 0.40, 3.13), a difference of 9.40 points (95% CI = 7.78, 11.01). During the pandemic, this difference decreased by 22.6% (2.05 points, 95% CI = 0.71, 3.40, p = .003) due to 0.89 points decrease in severity of scores in adolescents with depression (95% CI = 0.08, 1.70, p = .032) and 1.16 points increase in HVs' depressive symptoms (95% CI = 0.10, 2.23, p = .032). Compared to their pre-pandemic levels, adolescents with depression reported overall lower anxiety symptoms during the pandemic. Parent-on-child reports also were consistent with these results. CONCLUSION: Contrary to our hypothesis, we found that both depressive and anxiety symptoms were lower for adolescents with depression during the pandemic compared to before. In contrast, the depression scores for the HVs were higher during the pandemic relative to their pre-pandemic ratings; these scores remained much lower than those of adolescents with depression. CLINICAL TRIAL REGISTRATION INFORMATION: Characterization and Treatment of Adolescent Depression; https://clinicaltrials.gov/; NCT03388606.

Editorial: Not the Same as Adults: Vortioxetine in Adolescents With Major Depression.

In this issue, readers can review a multisite, double-blind, randomized, controlled trial (DBRCT) of vortioxetine for adolescent major depression (AMD) by Findling et al.1 The investigators deserve credit for this industry-sponsored study's several innovations: initial treatment following current guidelines, efforts to reduce placebo response rates (PRRs), and creation of both placebo- and active-control arms. The Journal deserves our respect for its commitment to highlighting these innovations, despite the trial's negative result. It is essential to perform treatment studies in adolescents, and this study underscores the fallacy of presuming that drugs showing efficacy in adults will be as effective in our patients.

Clinical utility of family history of depression for prognosis of adolescent depression severity and duration assessed with predictive modeling.

BACKGROUND: Family history of depression (FHD) is a known risk factor for the new onset of depression. However, it is unclear if FHD is clinically useful for prognosis in adolescents with current, ongoing, or past depression. This preregistered study uses a longitudinal, multi-informant design to examine whether a child's FHD adds information about future depressive episodes and depression severity applying state-of-the-art predictive out-of-sample methodology. METHODS: We examined data in adolescents with current or past depression (age 11-17 years) from the National Institute of Mental Health Characterization and Treatment of Adolescent Depression (CAT-D) study. We asked whether a history of depression in a first-degree relative was predictive of depressive episode duration (72 participants) and future depressive symptom severity in probands (129 participants, 1,439 total assessments). RESULTS: Family history of depression, while statistically associated with time spent depressed, did not improve predictions of time spent depressed, nor did it improve models of change in depression severity measured by self- or parent-report. CONCLUSIONS: Family history of depression does not improve the prediction of the course of depression in adolescents already diagnosed with depression. The difference between statistical association and predictive models highlights the importance of assessing predictive performance when evaluating questions of clinical utility.

A Randomized Controlled Trial of Computerized Interpretation Bias Training for Disruptive Mood Dysregulation Disorder: A Fast-Fail Study.

OBJECTIVE: To examine targeted, mechanism-based interventions is the next generation of treatment innovation. Biased threat labeling of ambiguous face emotions (interpretation bias) is a potential behavioral treatment target for anger, aggression, and irritability. Changing biases in face-emotion labeling may improve irritability-related outcomes. Here, we report the first randomized, double-blind, placebo-controlled targeted trial of interpretation bias training (IBT) in youths with chronic, severe irritability. METHOD: Patients with current disruptive mood dysregulation disorder (DMDD; N = 44) were randomly assigned to complete 4 sessions of active (n = 22) or sham (n = 22) computerized IBT training within a 1-week period. The first and last trainings were completed onsite, and 2 trainings were completed at home. We examined the effects of active IBT on labeling bias, primary outcome measures of irritability, and secondary outcome measures of anxiety, depression, and functional impairment. Follow-up assessments were completed immediately after the intervention as well as 1 and 2 weeks later. RESULTS: We found that active IBT engaged the behavioral target in the active relative to the sham condition, as shown by a significant shift toward labeling ambiguous faces as happy. However, there was no consistent clinical improvement in active IBT relative to the sham condition either immediately after or 2 weeks after training in either the primary or secondary outcome measures. CONCLUSION: Although this randomized controlled trial of IBT in youths with DMDD engaged the proposed behavioral target, there was no statistically significant improvement on clinical outcome. Identifying and changing behavioral targets is a first step in novel treatment development; these results have broader implications for target-based intervention development. CLINICAL TRIAL REGISTRATION INFORMATION: Psychological Treatments for Youth With Severe Irritability; https://clinicaltrials.gov/; NCT02531893.

Repetitive Transcranial Magnetic Stimulation for Adolescent Major Depressive Disorder: A Focus on Neurodevelopment.

Adolescent depression is a potentially lethal condition and a leading cause of disability for this age group. There is an urgent need for novel efficacious treatments since half of adolescents with depression fail to respond to current therapies and up to 70% of those who respond will relapse within 5 years. Repetitive transcranial magnetic stimulation (rTMS) has emerged as a promising treatment for major depressive disorder (MDD) in adults who do not respond to pharmacological or behavioral interventions. In contrast, rTMS has not demonstrated the same degree of efficacy in adolescent MDD. We argue that this is due, in part, to conceptual and methodological shortcomings in the existing literature. In our review, we first provide a neurodevelopmentally focused overview of adolescent depression. We then summarize the rTMS literature in adult and adolescent MDD focusing on both the putative mechanisms of action and neurodevelopmental factors that may influence efficacy in adolescents. We then identify limitations in the existing adolescent MDD rTMS literature and propose specific parameters and approaches that may be used to optimize efficacy in this uniquely vulnerable age group. Specifically, we suggest ways in which future studies reduce clinical and neural heterogeneity, optimize neuronavigation by drawing from functional brain imaging, apply current knowledge of rTMS parameters and neurodevelopment, and employ an experimental therapeutics platform to identify neural targets and biomarkers for response. We conclude that rTMS is worthy of further investigation. Furthermore, we suggest that following these recommendations in future studies will offer a more rigorous test of rTMS as an effective treatment for adolescent depression.

A preliminary study on functional activation and connectivity during frustration in youths with bipolar disorder.

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 activation and connectivity in the brain of BD youths in response to frustration. This exploratory study compared BD youths and HV on attentional abilities, self-reported affect, and functional activation and connectivity during a frustrating attention task. METHODS: Twenty BD (Mage  = 15.86) and 20 HV (Mage  = 15.55) youths completed an fMRI paradigm that differentiated neural responses during processing of frustrating feedback from neural responses during attention orienting following frustrating feedback. We examined group differences in (a) functional connectivity using amygdala, inferior frontal gyrus (IFG), and striatum as seeds and (b) whole-brain and regions of interest (amygdala, IFG, striatum) activation. We explored task performance (accuracy, reaction time), self-reported frustration and unhappiness, and correlations between these variables and irritability, depressive, and manic symptoms. RESULTS: Bipolar disorder youths, relative to HV, exhibited positive IFG-ventromedial prefrontal cortex (vmPFC) connectivity yet failed to show negative striatum-insula connectivity during feedback processing. Irritability symptoms were positively associated with striatum-insula connectivity during feedback processing. Moreover, BD vs HV youths showed positive IFG-parahippocampal gyrus (PHG)/periaqueductal gray (PAG) connectivity and negative amygdala-cerebellum connectivity during attention orienting following frustration. BD was not associated with atypical activation patterns. CONCLUSIONS: Positive IFG-vmPFC connectivity and striatum-insula decoupling in BD during feedback processing may mediate heightened sensitivity to reward-relevant 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 Clinician Affective Reactivity Index: Validity and Reliability of a Clinician-Rated Assessment of Irritability.

Irritability is impairing in youth and is the core feature of disruptive mood dysregulation disorder (DMDD). Currently, there are no established clinician-rated instruments to assess irritability in pediatric research and clinical settings. Clinician-rated measures ensure consistency of assessment across patients and are important specifically for treatment research. Here, we present data on the psychometric properties of the Clinician Affective Reactivity Index (CL-ARI), the first semistructured interview focused on pediatric irritability. The CL-ARI was administered to a transdiagnostic sample of 98 youth (M age = 12.66, SD = 2.47; 41% female). With respect to convergent validity, CL-ARI scores were (a) significantly higher for youth with DMDD than for any other diagnostic group, and (b) showed uniquely strong associations with other clinician-, parent-, and youth-report measures of irritability compared to measures of related constructs, such as anxiety. The three subscales of the CL-ARI (temper outbursts, irritable mood, impairment) showed excellent internal consistency. Test-retest reliability of the CL-ARI was adequate. These data support that irritability can be feasibly, validly, and reliably assessed by clinicians using the CL-ARI. A validated, gold-standard assessment of pediatric irritability is critical in advancing research and treatment efforts.

White matter microstructure in youth with and at risk for bipolar disorder.

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

A Double-Blind Randomized Placebo-Controlled Trial of Citalopram Adjunctive to Stimulant Medication in Youth With Chronic Severe Irritability.

OBJECTIVE: Despite the clinical importance of chronic and severe irritability, there is a paucity of controlled trials for its pharmacological treatment. Here, we examine the effects of adding citalopram (CTP) to methylphenidate (MPH) in the treatment of chronic severe irritability in youth using a double-blind randomized placebo-controlled design. METHOD: After a lead-in phase of open treatment with stimulant, 53 youth meeting criteria for severe mood dysregulation (SMD) were randomly assigned to receive CTP or placebo (PBO) for 8 weeks. A total of 49 participants, 48 of them (98%) meeting disruptive mood dysregulation disorder (DMDD) criteria, were included in the intent-to-treat analysis. The primary outcome measure was the proportion of response based on improvements of irritability at the week 8 of the trial. RESULTS: At the end of the trial, a significantly higher proportion of response was seen in those participants randomly assigned to CTP+MPH compared to PBO+MPH (35% CTP+MPH versus 6% PBO+MPH; odds ratio = 11.70, 95% CI = 2.00-68.16, p = 0.006). However, there were no differences in functional impairment between groups at the end of the trial. No differences were found in any adverse effect between treatment groups, and no trial participant exhibited hypomanic or manic symptoms. CONCLUSION: Adjunctive CTP might be efficacious in the treatment of chronic severe irritability in youth resistant to stimulant treatment alone. CLINICAL TRIAL REGISTRATION INFORMATION: A Controlled Trial of Serotonin Reuptake Inhibitors Added to Stimulant Medication in Youth With Severe Mood Dysregulation; https://clinicaltrials.gov; NCT00794040.

White Matter Microstructure in Pediatric Bipolar Disorder and Disruptive Mood Dysregulation Disorder.

OBJECTIVE: Disruptive mood dysregulation disorder (DMDD) codifies severe, chronic irritability. Youths with bipolar disorder (BD) also present with irritability, but with an episodic course. To date, it is not clear whether aberrant white matter microstructure-a well-replicated finding in BD-can be observed in DMDD and relates to symptoms of irritability. METHOD: We acquired diffusion tensor imaging data from 118 participants (BD = 36, DMDD = 44, healthy volunteers (HV = 38). Images of fractional anisotropy (FA), axial diffusivity (AD), and radial diffusivity (RD) were processed with tract-based spatial statistics controlling for age and sex. The data were also used to train Gaussian process classifiers to predict diagnostic group. RESULTS: In BD vs DMDD, FA in the corticospinal tract was reduced. In DMDD vs HV, reductions in FA and AD were confined to the anterior corpus callosum. In BD vs HV, widespread reductions in FA and increased RD were observed. FA in the anterior corpus callosum and corticospinal tract was negatively associated with irritability. The Gaussian process classifier could not discriminate between BD and DMDD, but achieved 68% accuracy in predicting DMDD vs HV and 75% accuracy in predicting BD vs HV. CONCLUSION: Aberrant white matter microstructure was associated with both categorical diagnosis and the dimension of irritability. Alterations in DMDD were regionally discrete and related to reduced AD. In BD, we observed widespread increases in RD, supporting the hypothesis of altered myelination in BD. These findings will contribute to the pathophysiological understanding of DMDD and its differentiation from BD. CLINICAL TRIAL REGISTRATION INFORMATION: Studies of Brain Function and Course of Illness in Pediatric Bipolar Disorder; https://clinicaltrials.gov/; NCT00025935; Child & Adolescent Bipolar Disorder Brain Imaging and Treatment Study; https://clinicaltrials.gov/; NCT00006177.

Parsing neurodevelopmental features of irritability and anxiety: Replication and validation of a latent variable approach.

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

Neural mechanisms of face emotion processing in youths and adults with bipolar disorder.

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

Brain Mechanisms of Attention Orienting Following Frustration: Associations With Irritability and Age in Youths.

OBJECTIVE: Childhood irritability is a common, impairing problem with changing age-related manifestations that predict long-term adverse outcomes. However, more investigation of overall and age-specific neural correlates is needed. Because youths with irritability exhibit exaggerated responses to frustrating stimuli, the authors used a frustration functional MRI (fMRI) paradigm to examine associations between irritability and neural activation and tested the moderating effect of age. METHOD: The authors studied a transdiagnostic sample of 195 youths with varying levels of irritability (disruptive mood dysregulation disorder, N=52; anxiety disorder, N=42; attention deficit hyperactivity disorder, N=40; and healthy volunteers, N=61). Irritability was measured by parent and child reports on the Affective Reactivity Index. The fMRI paradigm was a cued-attention task differentiating neural activity in response to frustration (rigged feedback) from activity during attention orienting in the trial following frustration. RESULTS: Whole-brain activation analyses revealed associations with irritability during attention orienting following frustration. Irritability was positively associated with frontal-striatal activation, specifically in the dorsolateral prefrontal cortex, inferior frontal gyrus, and caudate. Age moderated the association between irritability and activation in some frontal and posterior regions (the anterior cingulate cortex, medial frontal gyrus, cuneus, precuneus, and superior parietal lobule [F=19.04-28.51, df=1, 189, partial eta squared=0.09-0.13]). Specifically, higher irritability was more strongly related to increased activation in younger youths compared with older youths. CONCLUSIONS: Following frustration, levels of irritability correlated with activity in neural systems mediating attention orienting, top-down regulation of emotions, and motor execution. Although most associations were independent of age, dysfunction in the anterior cingulate cortex and posterior regions was more pronounced in young children with irritability.

Anticipatory Effects on Perceived Pain: Associations With Development and Anxiety.

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

Reliability of neural activation and connectivity during implicit face emotion processing in youth.

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

A Latent Variable Approach to Differentiating Neural Mechanisms of Irritability and Anxiety in Youth.

Importance: Comorbidity is ubiquitous in psychiatry, but it is unclear how to differentiate neural mechanisms of co-occurring symptoms. Pediatric irritability and anxiety symptoms are prevalent and frequently co-occur. Threat orienting is pertinent to both phenotypes and is an ideal context in which to examine their unique and common neural mechanisms. Objectives: To decompose the unique and shared variances of pediatric irritability and anxiety symptoms and to determine neural correlates of these differentiated phenotypes during threat orienting. Design, Setting, and Participants: This investigation was a cross-sectional functional magnetic resonance imaging study. The setting was a research clinic at the National Institute of Mental Health. Participants were youth aged 8 to 18 years spanning multiple diagnostic categories (141 youth with disruptive mood dysregulation disorder, anxiety disorder, and/or attention-deficit/hyperactivity disorder and 56 healthy youth). This combination provided wide variation in levels of irritability and anxiety symptoms. Data were acquired between June 30, 2012, and June 28, 2016. Main Outcomes and Measures: Participants and parents rated youth's irritability on the Affective Reactivity Index and anxiety on the Screen for Child Anxiety Related Emotional Disorders. Bifactor analysis decomposed the unique and shared variances. A functional magnetic resonance imaging dot-probe task assessed attention orienting to angry (ie, threat) vs neutral faces. Whole-brain analyses examined associations between the bifactor-derived phenotypes and both neural activity and amygdala functional connectivity. Results: Among 197 participants included in the final analysis, the mean (SD) age was 13.1 (2.7) years, and 91 (46.2%) were female. The best-fit bifactor model (Comparative Fit Index, 0.959; Root Mean Square Error of Approximation, 0.066) included unique factors of parent-reported irritability, youth-reported irritability, and anxiety, as well as a common factor of negative affectivity. When the task required attention away from threat, higher parent-reported irritability was associated with increased activity in the insula, caudate, dorsolateral and ventrolateral prefrontal cortex, and inferior parietal lobule (t189≥4.15 for all, P < .001 for all). In contrast, higher anxiety was associated with decreased amygdala connectivity to the cingulate, thalamus, and precentral gyrus (t189≤-4.19 for all, P < .001 for all). These distinctive neural correlates did not emerge using a diagnostic approach. Conclusions and Relevance: A latent variable approach to parsing co-occurring symptom dimensions revealed a novel double dissociation. During orientation away from threat, only irritability was associated with neural activity, whereas only anxiety was associated with amygdala connectivity. Despite the challenges of symptom co-occurrence for clinical neuroscience, data-driven phenotyping may facilitate a path forward.

Clinical Correlates of Carbon Dioxide Hypersensitivity in Children.

OBJECTIVE: Hypersensitivity to carbon dioxide (CO2)-enriched air may be a promising risk marker for anxiety disorders. Among adult and adolescent samples, heterogeneity in distress response to the CO2 challenge task indexes 3 underlying classes of individuals, which distinguish between sustained and acute threat response as markers for internalizing disorders, broadly, and anxiety disorders, specifically. The present study examines latent classes in children's response to the CO2 challenge task to clarify the association of CO2 hypersensitivity with anxiety and internalizing symptomatology in childhood. METHOD: Healthy children from a community twin sample (N = 538; age 9-13 years) rated anxious distress every 2 minutes while breathing air enriched to 7.5% CO2 for 8 minutes. Latent growth mixture modeling evaluated potential classes of individuals with characteristic trajectories of distress during the task to clarify the association with internalizing disorder symptoms and related traits (e.g., anxiety sensitivity, irritability). RESULTS: Although all participants reported increased distress during the task, interindividual heterogeneity in distress indexed 3 underlying classes: a consistently low class ("low"), a consistently high class ("high"), and participants who demonstrated markedly increased acute distress ("acute"). Compared to the low class, the high class reported greater internalizing psychopathology, whereas membership in the acute class was associated with experiencing a panic-like event during the task. CONCLUSION: As in older individuals, 3 distinct trajectories emerged to capture interindividual heterogeneity in children's distress during the CO2 challenge task. These classes were distinguished by clinical validators that reinforce the association of CO2 hypersensitivity and internalizing disorder phenotypes in children.

Latent structure of negative valence measures in childhood.

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.

Behavioral and Neural Sustained Attention Deficits in Disruptive Mood Dysregulation Disorder and Attention-Deficit/Hyperactivity Disorder.

OBJECTIVE: Disruptive mood dysregulation disorder (DMDD), characterized by severe irritability, and attention-deficit/hyperactivity disorder (ADHD) are highly comorbid. This is the first study to characterize neural and behavioral similarities and differences in attentional functioning across these disorders. METHOD: Twenty-seven healthy volunteers, 31 patients with DMDD, and 25 patients with ADHD (8 to 18 years old) completed a functional magnetic resonance imaging attention task. Group differences in intra-subject variability in reaction time (RT) were examined. The present functional magnetic resonance imaging analytic approach precisely quantified trial-wise associations between RT and brain activity. RESULTS: Group differences manifested in the relation between RT and brain activity (all regions: p < .01, F > 2.54, partial eta-squared [ηp2] > 0.06). Patients with DMDD showed specific alterations in the right paracentral lobule, superior parietal lobule, fusiform gyrus, and cerebellar culmen. In contrast, patients with DMDD and those with ADHD exhibited blunted compensatory increases in activity on long RT trials. In addition, youth with DMDD exhibited increased activity in the postcentral gyrus, medial frontal gyrus, and cerebellar tonsil and declive (all regions: p < .05, F > 2.46, ηp2 > 0.06). Groups in the imaging sample did not differ significantly in intra-subject variability in RT (F2,79 = 2.664, p = .076, ηp2 = 0.063), although intra-subject variability in RT was significantly increased in youth with DMDD and ADHD when including those not meeting strict motion and accuracy criteria for imaging analysis (F2,96 = 4.283, p = .017, ηp2 = 0.083). CONCLUSION: Patients with DMDD exhibited specific alterations in the relation between pre-stimulus brain activity and RT. Patients with DMDD and those with ADHD exhibited similar blunting of compensatory neural activity in frontal, parietal, and other regions. In addition, patients with DMDD showed increased RT variability compared with healthy youth. This work is the first to identify common and unique behavioral and neural signatures of DMDD and ADHD.