Neural Responses to Intranasal Oxytocin in Youths With Severe Irritability.

OBJECTIVE: The authors investigated the neural impact of intranasal oxytocin on emotion processing areas in youths with severe irritability in the context of disruptive mood and behavior disorders. METHODS: Fifty-two participants with severe irritability, as measured by a score ≥4 on the Affective Reactivity Index (ARI), with diagnoses of disruptive behavior disorders (DBDs) and/or disruptive mood dysregulation disorder (DMDD) were randomly assigned to treatment with intranasal oxytocin or placebo daily for 3 weeks. Assessments were conducted at baseline and at the end of the trial; the primary outcomes were measures of irritability on the ARI and ratings on the Clinical Global Impressions severity scale (CGI-S) focusing on DBD and DMDD symptoms, and secondary outcomes included the CGI improvement scale (CGI-I) and ratings of proactive and reactive aggressive behavior on the Reactive-Proactive Aggression Questionnaire. Forty-three participants (22 in the oxytocin group and 21 in the placebo group) completed pre- and posttreatment functional MRI (fMRI) scans with the affective Stroop task. RESULTS: Youths who received oxytocin showed significant improvement in CGI-S and CGI-I ratings compared with those who received placebo. In the fMRI data, blood-oxygen-level-dependent (BOLD) responses to emotional stimuli in the dorsomedial prefrontal cortex and posterior cingulate cortex were significantly reduced after oxytocin compared with placebo. These BOLD response changes were correlated with improvement in clinical severity. CONCLUSIONS: This study provides initial and preliminary evidence that intranasal oxytocin may induce neural-level changes in emotion processing in youths with irritability in the context of DBDs and DMDD. This may lead to symptom and severity changes in irritability.

Mediating effect of amygdala activity on response to fear vs. happiness in youth with significant levels of irritability and disruptive mood and behavior disorders.

Introduction: Irritability, characterized by a tendency to exhibit increased anger, is a common clinical problem in youth. Irritability is a significant clinical issue in youth with various psychiatric diagnoses, especially disruptive behavior, and mood disorders (Attention-Deficit/Hyperactivity Disorder, Oppositional Defiant Disorder, Conduct Disorder, and Disruptive Mood Dysregulation Disorder). Although there have been previous studies focusing on functional alteration in the amygdala related to irritability, there is no comprehensive model between emotional, neuronal, and behavioral characteristics. Methods: Using an functional magnetic resonance imaging (fMRI) procedure, we investigated the relationships between behavioral irritability, selective impairments in processing facial emotions and the amygdala neural response in youth with increased irritability. Fifty-nine youth with disruptive mood and behavior disorder completed a facial expression processing task with an event-related fMRI paradigm. The severity of irritability was evaluated using the Affective Reactivity Index. Results: In the result of behavioral data, irritability, and reaction time (RT) differences between interpreting negative (fear) and positive (happiness) facial expressions were positively correlated. In the fMRI result, youth showed higher activation in the right cingulate gyrus, bilateral cerebellum, right amygdala, right precuneus, right superior frontal gyrus, right middle occipital gyrus, and middle temporal gyrus, during the happiness condition vs. fear condition. No brain region exhibited greater activation in the fear than in the happiness conditions. In the result of the mediator analysis, increased irritability was associated with a longer RT toward positive vs. negative facial expressions. Irritability was also positively associated with the difference in amygdala blood oxygen level-dependent responses between the two emotional conditions (happiness > fear). This difference in amygdala activity mediated the interaction between irritability and the RT difference between negative and positive facial expressions. Discussion: We suggest that impairment in the implicit processing of facial emotional expressions with different valences causes distinct patterns of amygdala response, which correlate with the level of irritability. These results broaden our understanding of the biological mechanism of irritability at the neural level and provide information for the future direction of the study.

Research Audit on Clinical Utility of Dimensional Disruptive Mood and Behavior Psychopathologies in Child and Adolescent Psychiatry Practice.

To investigate the utility of dimensional psychopathologies of disruptive mood and behavior disorders (DBDs) by applying latent profile analysis (LPA) for characterization of youth referred to the tertiary outpatient clinic of child and adolescent psychiatry clinic and pharmacological treatment choices. One hundred fifty-eight children and adolescents with significant DBDs symptoms participated. Core dimensional psychopathologies of DBDs (irritability, callous-unemotional trait, and reactive-proactive aggressive behavior), DSM diagnoses, prescribed medications, and behavioral and emotional problems (Child Behavior Checklist, CBCL) were measured at baseline (clinic intake) and at 3-month follow-up. Latent Profile Analysis (LPA) was applied to characterize the study population based on the levels and interrelations among the core dimensional DBDs psychopathologies. Following LPA, the differences in clinical and treatment features between the latent classes were analyzed. LPA revealed two latent classes based on severity of DBDs symptoms. Class 1 (the moderate group) was characterized by relatively low scores on all trans-diagnostic indicators, whereas class 2 (the severe/critical group) showed higher levels of the dimensional psychopathologies and the majority of CBCL subscales. In addition, the severe/critical group was more often prescribed antipsychotic medications, and also experienced more frequent medication changes (addition, increasing the dose, and trial of different medications). Our findings suggested that application of LPA to a cluster of dimensional DBDs psychopathologies may provide valuable characterization of the youths referred to a tertiary outpatient child and adolescent psychiatric clinic, and offer insight into the providers' decision making on psychotropic medications, by overall severity of these psychopathologies rather than by single categorical diagnosis or single externalizing psychopathology.

Functional and Structural Alteration of Default Mode, Executive Control, and Salience Networks in Alcohol Use Disorder.

Alcohol use disorder (AUD) has been related to aberrant functional connectivity (FC) in the salience network (SN), executive control network (ECN), and default mode network (DMN). However, there is a lack of comprehensive and simultaneous examination of these networks in patients with AUD and of their relation to potential anatomical changes. We aimed to comprehensively examine the alteration in FC in the three networks in AUD patients, and the correlation of the alteration with anatomical/structural changes (volume) in the neural areas implicated in these networks, by applying voxel-based morphometry (VBM) and region of interest-to-region of interest connectivity analysis simultaneously. In all, 22 patients with AUD and 22 healthy adults participated in the study and underwent T1 magnetic resonance imaging. Patients with AUD showed increased FCs within the DMN and SN networks, especially in terms of connectivity of the frontal areas and bilateral hippocampi. They also showed decreased FCs in the ECN. In addition, there was significant volume reduction in these areas (frontal areas and hippocampus). The increased FCs within the frontal areas or bilateral hippocampi showed a negative correlation with gray matter volume of these areas in AUD patients. Our findings add to the empirical evidence that the frontal lobe and hippocampi are critical areas that are vulnerable to functional and structural changes due to AUD.

Neural Responses to Fluoxetine in Youths with Disruptive Behavior and Trauma Exposure: A Pilot Study.

Objective: A preliminary investigation of the impact of a serotonergic agent (fluoxetine) on symptom profile and neural response in youths with disruptive behavior disorders (DBDs) and a history of trauma exposure. Methods: There were three participant groups: (i) Youths with DBDs and trauma exposure who received fluoxetine treatment for 8 weeks (n = 11); (ii) A matched group of youths with DBDs and trauma exposure who received routine regular follow-up in an outpatient clinic (n = 10); and (iii) Typically developing youths (n = 18). All participants conducted an expression processing functional magnetic resonance imaging task twice, 8 weeks apart: (pretreatment and post-treatment for youths with DBDs). Results: Youths with DBDs and trauma exposure who received fluoxetine treatment compared to the other two groups showed: (i) significant improvement in externalizing, oppositional defiant disorder, irritability, anxiety-depression, and trauma-related symptoms; (ii) as a function of fearful expression intensity, significantly decreased amygdala response and increased recruitment of regions implicated in top-down attention control (insula cortex, inferior parietal lobule, and postcentral gyrus) and emotional regulation (ventromedial prefrontal cortex [vmPFC]); and (iii) correlation between DBD/irritability symptom improvement and increased activation of top-down attention control areas (inferior parietal lobule, insula cortex, and postcentral gyrus) and an emotion regulation area (vmPFC). Conclusions: This study provides preliminary evidence that a serotonergic agent (fluoxetine) can reduce disruptive behavior and mood symptoms in youths with DBDs and trauma exposure and that this may be mediated by enhanced activation of top-down attention control and emotion regulation areas (inferior parietal lobule, insula cortex, and vmPFC).