Longitudinal Stability of Genetic and Environmental Influences on Irritability: From Childhood to Young Adulthood.

OBJECTIVE: Little is known about genetic influences on juvenile irritability and whether such influences are developmentally stable and/or dynamic. This study examined the temporal pattern of genetic and environmental effects on irritability using data from a prospective, four-wave longitudinal twin study. METHOD: Parents and their twin children (N=2,620 children) from the Swedish Twin Study of Child and Adolescent Development reported on the children's irritability, defined using a previously identified scale from the Child Behavior Checklist. RESULTS: Genetic effects differed across the sexes, with males exhibiting increasing heritability from early childhood through young adulthood and females exhibiting decreasing heritability. Genetic innovation was also more prominent in males than in females, with new genetic risk factors affecting irritability in early and late adolescence for males. Shared environment was not a primary influence on irritability for males or females. Unique, nonshared environmental factors suggested strong effects early for males followed by an attenuating influence, whereas unique environmental factors were relatively stable for females. CONCLUSIONS: Genetic effects on irritability are developmentally dynamic from middle childhood through young adulthood, with males and females displaying differing patterns. As males age, genetic influences on irritability increase while nonshared environmental influences weaken. Genetic contributions are quite strong in females early in life but decline in importance with age. In girls, nonshared environmental influences are fairly stable throughout development.The National Institutes of Health/National Institute of Mental HealthPublishe

Deficits in attention to emotional stimuli distinguish youth with severe mood dysregulation from youth with bipolar disorder.

Studying attention in the context of emotional stimuli may aid in differentiating pediatric bipolar disorder (BD) from severe mood dysregulation (SMD). SMD is characterized by chronic irritability, arousal, and hyper-reactivity; SMD youth frequently receive a BD diagnosis although they do not meet DSM-IV criteria for BD because they lack manic episodes. We compared 57 BD (14.4 +/- 2.9 years old, 56% male), 41 SMD (12.6 +/- 2.6 years old, 66% male), and 33 control subjects (13.7 +/- 2.5 years old, 52% male) using the Emotional Interrupt task, which examines how attention is impacted by positive, negative, or neutral distracters. We compared reaction time (RT) and accuracy and calculated attention interference scores by subtracting performance on neutral trials from emotional trials. Between-group analyses indicated that SMD subjects had significantly reduced attention interference from emotional distracters relative to BD and control subjects. Thus, attention in SMD youth was not modulated by emotional stimuli. This blunted response in SMD youth may contribute to their affective and behavioral dysregulation

A Developmental Study of the Neural Circuitry Mediating Motor Inhibition in Bipolar Disorder

OBJECTIVE: Despite increased interest in the developmental trajectory of the pathophysiology mediating bipolar disorder (BD), few studies compare adults and youths with BD. Deficits in motor inhibition are thought to play an important role in the pathophysiology of BD across the age spectrum. Here we compare neural circuitry mediating this process in youths vs. adults with BD and healthy volunteers. METHOD: fMRI data from 89 subjects (16 BD youth, 23 BD adults, 21 healthy children, 29 healthy adults) were acquired while subjects performed the stop-signal task. RESULTS: During failed inhibition, an age group x diagnosis interaction manifested in the anterior cingulate cortex (ACC), with child BD participants showing hypoactivation relative to healthy children and adult BD, and adult BD showing hyperactivation relative to healthy adults. During successful inhibition, a main effect of diagnosis emerged in the right nucleus accumbens and left ventral prefrontal cortex, with bipolar individuals, irrespective of age, showing less activation than healthy participants. CONCLUSIONS: Child BD and adult BD both show ACC dysfunction during failed motor inhibition, although the nature of that dysfunction differs between groups. Adults and youth with BD show similar deficits in nucleus accumbens and ventral prefrontal cortex activation during successful inhibition. Therefore, while subcortical and VPFC hypoactivation is present in BD across the lifespan, ACC dysfunction varies developmentally, with reduced ACC activation in child BD and increased activation in adult BD during failed inhibition. Longitudinal fMRI studies on the developmental trajectory of the neural circuitry mediating motor inhibition in BD are warranted

Specificity of facial expression labeling deficits in childhood psychopathology

Background: We examined whether face-emotion labeling deficits are illness-specific or an epiphenomenon of generalized impairment in pediatric psychiatric disorders involving mood and behavioral dysregulation. Method: Two hundred fifty-two youths (7-18 years old) completed child and adult facial expression recognition subtests from the Diagnostic Analysis of Nonverbal Accuracy (DANVA) instrument. Forty-two participants had bipolar disorder (BD), 39 had severe mood dysregulation (SMD; i.e., chronic irritability, hyperarousal without manic episodes), 44 had anxiety and/or major depressive disorders (ANX/MDD), 35 had attention-deficit/hyperactivity and/or conduct disorder (ADHD/CD), and 92 were controls. Dependent measures were number of errors labeling happy, angry, sad, or fearful emotions. Results: BD patients made more errors than ANX/MDD, ADHD/CD, or controls when labeling all emotional expressions, whether those expressions were on the faces of children or adults. SMD also showed emotion-labeling deficits, in particular as compared to ANX/MDD patients and controls. Conclusions: Face-emotion labeling deficits differentiate BD and SMD patients from those with ANX/MDD or ADHD/CD and controls. The extent to which such deficits cause vs. result from emotional dysregulation requires further study

Association of Irritability and Anxiety With the Neural Mechanisms of Implicit Face Emotion Processing in Youths With Psychopathology

Importance: Psychiatric comorbidity complicates clinical care and confounds efforts to elucidate the pathophysiology of commonly occurring symptoms in youths. To our knowledge, few studies have simultaneously assessed the effect of 2 continuously distributed traits on brain-behavior relationships in children with psychopathology. Objective: To determine shared and unique effects of 2 major dimensions of child psychopathology, irritability and anxiety, on neural responses to facial emotions during functional magnetic resonance imaging. Design, Setting, and Participants: Cross-sectional functional magnetic resonance imaging study in a large, well-characterized clinical sample at a research clinic at the National Institute of Mental Health. The referred sample included youths ages 8 to 17 years, 93 youths with anxiety, disruptive mood dysregulation, and/or attention-deficit/hyperactivity disorders and 22 healthy youths. Main Outcomes and Measures: The child's irritability and anxiety were rated by both parent and child on the Affective Reactivity Index and Screen for Child Anxiety Related Disorders, respectively. Using functional magnetic resonance imaging, neural response was measured across the brain during gender labeling of varying intensities of angry, happy, or fearful face emotions. In mixed-effects analyses, the shared and unique effects of irritability and anxiety were tested on amygdala functional connectivity and activation to face emotions. Results: The mean (SD) age of participants was 13.2 (2.6) years; of the 115 included, 64 were male. Irritability and/or anxiety influenced amygdala connectivity to the prefrontal and temporal cortex. Specifically, irritability and anxiety jointly influenced left amygdala to left medial prefrontal cortex connectivity during face emotion viewing (F4,888 = 9.20; P < .001 for mixed model term). During viewing of intensely angry faces, decreased connectivity was associated with high levels of both anxiety and irritability, whereas increased connectivity was associated with high levels of anxiety but low levels of irritability (Wald χ21 = 21.3; P < .001 for contrast). Irritability was associated with differences in neural response to face emotions in several areas (F2, 888 ≥ 13.45; all P < .001). This primarily occurred in the ventral visual areas, with a positive association to angry and happy faces relative to fearful faces. Conclusions and Relevance: These data extend prior work conducted in youths with irritability or anxiety alone and suggest that research may miss important findings if the pathophysiology of irritability and anxiety are studied in isolation. Decreased amygdala-medial prefrontal cortex connectivity may mediate emotion dysregulation when very anxious and irritable youth process threat-related faces. Activation in the ventral visual circuitry suggests a mechanism through which signals of social approach (ie, happy and angry expressions) may capture attention in irritable youth

An Open Pilot Study of Training Hostile Interpretation Bias to Treat Disruptive Mood Dysregulation Disorder

Objective: Irritability in disruptive mood dysregulation disorder (DMDD) may be associated with a biased tendency to judge ambiguous facial expressions as angry. We conducted three experiments to explore this bias as a treatment target. We tested: 1) whether youth with DMDD express this bias; 2) whether judgment of ambiguous faces can be altered in healthy youth by training; and 3) whether such training in youth with DMDD is associated with reduced irritability and associated changes in brain function. Methods: Participants in all experiments made happy versus angry judgments of faces that varied along a happy to angry continuum. These judgments were used to quantify a “balance point,” the facial expression at which a participant's judgment switches from predominantly happy to predominantly angry. We first compared balance points in youth with DMDD (n = 63) versus healthy youth (n = 26). We then conducted a double-blind, randomized controlled trial of active versus sham balance-point training in 19 healthy youth. Finally, we piloted open, active balance-point training in 14 youth with DMDD, with 10 completing an implicit functional MRI (fMRI) face-emotion processing task. Results: Relative to healthy youth, DMDD youth manifested a shifted balance point, expressed as a tendency to classify ambiguous faces as angry rather than happy. In both healthy and DMDD youth, active training is associated with a shift in balance point toward more happy judgments. In DMDD, evidence suggests that active training may be associated with decreased irritability and changes in activation in the lateral orbitofrontal cortex. Conclusions:These results set the stage for further research on computer-based treatment targeting interpretation bias of angry faces in DMDD. Such treatment may decrease irritability and alter neural responses to subtle expressions of happiness and anger

Efficacy and mechanisms underlying a gamified attention bias modification training in anxious youth: protocol for a randomized controlled trial

Background Attention bias modification training (ABMT) and cognitive behavioral therapy (CBT) likely target different aspects of aberrant threat responses in anxiety disorders and may be combined to maximize therapeutic benefit. However, studies investigating the effect of ABMT in the context of CBT have yielded mixed results. Here, we propose an enhanced ABMT to target the attentional bias towards threat, in addition to classic CBT for anxiety disorders in youth. This enhanced ABMT integrates the modified dot-probe task used in previous studies, where a target is always presented at the previous location of the neutral and not the simultaneously presented threatening stimulus, with a visual search, where the targets are always presented distally of threatening distractors. These two training elements (modified dot-probe and visual search) are embedded in an engaging game to foster motivation and adherence. Our goal is to determine the efficacy of the enhanced ABMT in the context of CBT. Further, we aim to replicate two previous findings: (a) aberrant amygdala connectivity being the neurobiological correlate of the attentional bias towards threat at baseline; and (b) amygdala connectivity being a mediator of the ABMT effect. We will also explore moderators of treatment response (age, sex, depressive symptoms and irritability) on a behavioral and neuronal level. Methods One hundred and twenty youth (8–17 years old) with a primary anxiety disorder diagnosis all receive CBT and are randomized to nine weeks of either active or control ABMT and symptom improvement will be compared between the two study arms. We will also recruit 60 healthy comparison youth, who along with eligible anxious youth, will be assessed with the dot-probe task during fMRI (anxious youth: before and after training; healthy volunteers: second measurement twelve weeks after initial assessment). Discussion The present study will contribute to the literature by (1) potentially replicating that aberrant amygdala connectivity mediates the attentional bias towards threat in anxious youth; (2) determining the efficacy of enhanced ABMT; and (3) advancing our understanding of the mechanisms underlying ABMT. Trial registration Clinicaltrials.gov: NCT03283930 Trial registration date: September 14th 2017. The trial registration took place retrospectively. Data acquisition started February 1st 2017

A double-blind, randomized, placebo-controlled trial of a computer-based Interpretation Bias Training for youth with severe irritability:a study protocol

Abstract Background Severe, chronic, and impairing irritability is a common presenting clinical problem in youth. Indeed, it was recently operationalized as disruptive mood dysregulation disorder (DMDD) in the DSM-5. However, to date, there are no evidence-based treatments that were specifically developed for DMDD. The current randomized controlled trial assesses the efficacy of a computer-based cognitive training intervention (Interpretation Bias Training; IBT) in youth with DMDD. IBT aims to reduce irritability by altering judgments of ambiguous face-emotions through computerized feedback. IBT is based on previous findings that youth with irritability-related psychopathology rate ambiguous faces as more hostile and fear producing. Methods/design This is a double-blind, randomized controlled trial of IBT in 40 youth with DMDD. Participants will be randomized to receive four IBT sessions (Active vs. Sham training) over 4 days. Active IBT provides computerized feedback to change ambiguous face-emotion interpretations towards happy interpretations. Face-emotion judgments are performed pre and post training, and for 2 weeks following training. Blinded clinicians will conduct weekly clinical ratings. Primary outcome measures assess changes in irritability using the clinician-rated Affective Reactivity Index (ARI) and Clinical Global Impressions-Improvement (CGI-I) scale for DMDD, as well as parent and child reports of irritability using the ARI. Secondary outcome measures include clinician ratings of depression, anxiety, and overall impairment. In addition, parent and child self-report measures of depression, anxiety, anger, social status, and aggression will be collected. Discussion The study described in this protocol will perform the first RCT testing the efficacy of IBT in reducing irritability in youth with DMDD. Developing non-pharmacological treatment options for youth suffering from severe, chronic irritability is important to potentially augment existing treatments. Trial registration ClinicalTrials.gov, ID: NCT02531893. Registered on 25 August 2015

Differentiating irritable mood and disruptive behavior in adults

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

Comparison of Storage Conditions for Human Vaginal Microbiome Studies

BACKGROUND: The effect of storage conditions on the microbiome and metabolite composition of human biological samples has not been thoroughly investigated as a potential source of bias. We evaluated the effect of two common storage conditions used in clinical trials on the bacterial and metabolite composition of the vaginal microbiota using pyrosequencing of barcoded 16S rRNA gene sequencing and (1)H-NMR analyses. METHODOLOGY/PRINCIPAL FINDINGS: Eight women were enrolled and four mid-vaginal swabs were collected by a physician from each woman. The samples were either processed immediately, stored at -80°C for 4 weeks or at -20°C for 1 week followed by transfer to -80°C for another 4 weeks prior to analysis. Statistical methods, including Kolmogorovo-Smirnov and Wilcoxon tests, were performed to evaluate the differences in vaginal bacterial community composition and metabolites between samples stored under different conditions. The results showed that there were no significant differences between samples processed immediately after collection or stored for varying durations. (1)H-NMR analysis of the small molecule metabolites in vaginal secretions indicated that high levels of lactic acid were associated with Lactobacillus-dominated communities. Relative abundance of lactic acid did not appear to correlate with relative abundance of individual Lactobacillus sp. in this limited sample, although lower levels of lactic acid were observed when L. gasseri was dominant, indicating differences in metabolic output of seemingly similar communities. CONCLUSIONS/SIGNIFICANCE: These findings benefit large-scale, field-based microbiome and metabolomic studies of the vaginal microbiota