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Aberrant microstructure of the uncinate fasciculus (UNC), a white matter (WM) tract implicated in emotion regulation, has been hypothesized as a neurobiological mechanism of depression. However, studies testing this hypothesis have yielded inconsistent results. The present meta-analysis consolidates evidence from 44 studies comparing fractional anisotropy (FA) and radial diffusivity (RD), two metrics characterizing WM microstructure, of the UNC in individuals with depression (n = 5016) to healthy individuals (n = 18 425). We conduct meta-regressions to identify demographic and clinical characteristics that contribute to cross-study heterogeneity in UNC findings. UNC FA was reduced in individuals with depression compared to healthy individuals. UNC RD was comparable between individuals with depression and healthy individuals. Comorbid anxiety explained inter-study heterogeneity in UNC findings. Depression is associated with perturbations in UNC microstructure, specifically with respect to UNC FA and not UNC RD. The association between depression and UNC microstructure appears to be moderated by anxiety. Future work should unravel the cellular mechanisms contributing to aberrant UNC microstructure in depression; clarify the relationship between UNC microstructure, depression, and anxiety; and link UNC microstructure to psychological processes, such as emotion regulation.

Irritability, characterized by anger in response to frustration, is normative in childhood. While children typically show a decline in irritability from toddlerhood to school age, elevated irritability throughout childhood may predict later psychopathology. The current study (n = 78) examined associations between trajectories of irritability in early childhood (ages 2–7) and irritability in adolescence (age 12) and tested whether these associations are moderated by parenting behaviors. Results indicate that negative emotion socialization moderated trajectories of irritability – relative to children with low stable irritability, children who exhibited high stable irritability in early childhood and who had parents that exhibited greater negative emotion socialization behaviors had higher irritability in adolescence. Further, negative parental control behavior moderated trajectories of irritability – relative to children with low stable irritability, children who had high decreasing irritability in early childhood and who had parents who exhibited greater negative control behaviors had higher irritability in adolescence. In contrast, positive emotion socialization and control behaviors did not moderate the relations between early childhood irritability and later irritability in adolescence. These results suggest that both irritability in early childhood and negative parenting behaviors may jointly influence irritability in adolescence. The current study underscores the significance of negative parenting behaviors and could inform treatment.

Irritability is a transdiagnostic symptom dimension in developmental psychopathology, closely related to the Research Domain Criteria (RDoC) construct of frustrative nonreward. Consistent with the RDoC framework and calls for transdiagnostic, developmentally-sensitive assessment methods, we report data from a smartphone-based, naturalistic ecological momentary assessment (EMA) study of irritability. We assessed 109 children and adolescents (Mage = 12.55 years; 75.20% male) encompassing several diagnostic groups – disruptive mood dysregulation disorder (DMDD), attention-deficit/hyperactivity disorder (ADHD), anxiety disorders (ANX), healthy volunteers (HV). The participants rated symptoms three times per day for 1 week. Compliance with the EMA protocol was high. As tested using multilevel modeling, EMA ratings of irritability were strongly and consistently associated with in-clinic, gold-standard measures of irritability. Further, EMA ratings of irritability were significantly related to subjective frustration during a laboratory task eliciting frustrative nonreward. Irritability levels exhibited an expected graduated pattern across diagnostic groups, and the different EMA items measuring irritability were significantly associated with one another within all groups, supporting the transdiagnostic phenomenology of irritability. Additional analyses utilized EMA ratings of anxiety as a comparison with respect to convergent validity and transdiagnostic phenomenology. The results support new measurement tools that can be used in future studies of irritability and frustrative nonreward.

Early behaviors that differentiate later biomarkers for psychopathology can guide preventive efforts while also facilitating pathophysiological research. We test whether the 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. BI was assessed via maternal report and behavioral responses to novelty. Childhood irritability was assessed using the Child Behavior Checklist. At age 12, electroencephalogram (EEG) was recorded while children performed a flanker task to measure the 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 a 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.

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.

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

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

Face memory deficits may be a bipolar disorder (BD) endophenotype. BD (n = 27) and unaffected youth at risk (n = 13) exhibited middle frontal gyrus hypoactivation during successful vs. unsuccessful encoding. Parahippocampal gyrus dysfunction was found in BD and at-risk youth (vs. low-risk, n = 37). Middle occipital gyrus hypoactivation was only present in BD.

BackgroundDespite the inclusion of disruptive mood dysregulation disorder (DMDD) in DSM-5, little empirical data exist on the disorder. We estimated rates, co-morbidity, correlates and early childhood predictors of DMDD in a community sample of 6-year-olds.MethodDMDD was assessed in 6-year-old children (n = 462) using a parent-reported structured clinical interview. Age 6 years correlates and age 3 years predictors were drawn from six domains: demographics; child psychopathology, functioning, and temperament; parental psychopathology; and the psychosocial environment.ResultsThe 3-month prevalence rate for DMDD was 8.2% (n = 38). DMDD occurred with an emotional or behavioral disorder in 60.5% of these children. At age 6 years, concurrent bivariate analyses revealed associations between DMDD and depression, oppositional defiant disorder, the Child Behavior Checklist – Dysregulation Profile, functional impairment, poorer peer functioning, child temperament (higher surgency and negative emotional intensity and lower effortful control), and lower parental support and marital satisfaction. The age 3 years predictors of DMDD at age 6 years included child attention deficit hyperactivity disorder, oppositional defiant disorder, the Child Behavior Checklist – Dysregulation Profile, poorer peer functioning, child temperament (higher child surgency and negative emotional intensity and lower effortful control), parental lifetime substance use disorder and higher parental hostility.ConclusionsA number of children met DSM-5 criteria for DMDD, and the diagnosis was associated with numerous concurrent and predictive indicators of emotional and behavioral dysregulation and poor functioning.

BackgroundPreliminary research implicates threat-related attention biases in paediatric anxiety disorders. However, major questions exist concerning diagnostic specificity, effects of symptom-severity levels, and threat-stimulus exposure durations in attention paradigms. This study examines these issues in a large, community school-based sample.MethodA total of 2046 children (ages 6–12 years) were assessed using the Development and Well Being Assessment (DAWBA), Childhood Behavior Checklist (CBCL) and dot-probe tasks. Children were classified based on presence or absence of ‘fear-related’ disorders, ‘distress-related’ disorders, and behavioural disorders. Two dot-probe tasks, which differed in stimulus exposure, assessed attention biases for happy-face and threat-face cues. The main analysis included 1774 children.ResultsFor attention bias scores, a three-way interaction emerged among face-cue emotional valence, diagnostic group, and internalizing symptom severity (F = 2.87, p n = 1411, mean difference = 11.03, s.e. = 3.47, df = 1, p n = 66, mean difference = 10.63, s.e. = 5.24, df = 1, p n = 86, mean difference = −11.90, s.e. = 5.94, df = 1, p away from threat. These associations did not emerge in the behaviour-disorder group (n = 211).ConclusionsThe association between internalizing symptoms and biased orienting varies with the nature of developmental psychopathology. Both the form and severity of psychopathology moderates threat-related attention biases in children.

BackgroundFrom an affective neuroscience perspective, our understanding of psychiatric illness may be advanced by neuropsychological test paradigms probing emotional processes. Reversal learning is one such process, whereby subjects must first acquire stimulus/reward and stimulus/punishment associations through trial and error and then reverse them. We sought to determine the specificity of previously demonstrated reversal learning impairments in youths with bipolar disorder (BD) by now comparing BD youths to those with severe mood dysregulation (SMD), major depressive disorder (MDD), anxiety (ANX), and healthy controls.MethodWe administered the probabilistic response reversal (PRR) task to 165 pediatric participants aged 7–17 years with BD (n=35), SMD (n=35), ANX (n=42), MDD (n=18) and normal controls (NC; n=35). Our primary analysis compared PRR performance across all five groups matched for age, sex and IQ.ResultsCompared to typically developing controls, probabilistic reversal learning was impaired in BD youths, with a trend in those with MDD (p=0.07).ConclusionsOur results suggest that reversal learning deficits are present in youths with BD and possibly those with MDD. Further work is necessary to elucidate the specificity of neural mechanisms underlying such behavioral deficits.