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Although irritability is among the most common reasons that children and adolescents are brought for psychiatric care, there are few effective treatments. Developmentally sensitive pathophysiological models are needed to guide treatment development. In this review, the authors present a mechanistic model of irritability that integrates clinical and translational neuroscience research. Two complementary conceptualizations of pathological irritability are proposed: 1) aberrant emotional and behavioral responding to frustrative nonreward, mediated by reward-system dysfunction; and 2) aberrant approach responding to threat, mediated by threat-system dysfunction. The authors review the pathophysiological literature, including animal studies, as well as experimental psychology and clinical studies. Data suggest that, relative to healthy children, irritable children have deficient reward learning and elevated sensitivity to reward receipt and omission. These deficits are associated with dysfunction in the prefrontal cortex, striatum, and amygdala. Youths with irritability also show maladaptive orienting to, interpreting, and labeling of potential threats, associated with prefrontal cortical and amygdalar dysfunction. Abnormalities in reward and threat processing potentiate one another. Future work should test pathophysiological hypotheses and novel interventions targeting reward- and threat-related dysfunction to improve treatment for severe irritability in youths.

Major Depressive Disorder (MDD) is a prevalent disorder involving disturbances in mood. There is still much to understand regarding precisely how emotions are disrupted in individuals with MDD. In this study, we used a network approach to examine the emotional disturbances underlying MDD. We hypothesized that, compared to healthy controls, individuals diagnosed with MDD would be characterized by a denser emotion network, indicating that their emotion system is more resistant to change. Indeed, results from a 7-day experience sampling study revealed that individuals with MDD had a denser overall emotion network than did healthy controls. Moreover, this difference was driven primarily by a denser negative, but not positive, network in MDD participants. These findings suggest that the disruption in emotions that characterizes depressed individuals stems from a negative emotion system that is resistant to change.

Irritability is a common and impairing clinical presentation in children and adolescents. Despite its significant public health impact, irritability remains an elusive construct. Chronic and severe irritability is the primary symptom of the new DSM-5 diagnosis, disruptive mood dysregulation disorder (DMDD). However, empirical and clinical approaches to irritability are in their relative infancy, and questions regarding the validity of the DMDD diagnosis have been raised. Moreover, irritability is a trait distributed continuously in youth, thereby fitting within the National Institute of Mental Health Research Domain Criteria initiative. Thus, there are opportunities for scientific review and integration. Accordingly, the goals of this review include (a) clarifying the definitions of irritability, incorporating clinical and translational animal work; (b) reviewing the historical context surrounding the study of irritability;

Objective: Childhood irritability is a common, impairing problem with changing agerelated manifestations that predict long-term adverse outcomes. However, more work is needed on its overall and age-specific neural correlates. Since irritable youth exhibit exaggerated responses to frustrating stimuli, we used a frustrating functional magnetic resonance imaging (fMRI) paradigm to examine associations between irritability and neural activation and tested the moderating effect of age. Method: We studied a transdiagnostic sample of 195 youths with varying levels of irritability (52 disruptive mood dysregulation disorder, 42 anxiety disorder, 40 attention deficit/hyperactivity disorder, and 61 healthy volunteers). 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 frontalstriatal activation, specifically in dorsolateral prefrontal cortex, inferior frontal gyrus, and caudate (rs=.31-.40, ps<.05). Age moderated the association between irritability and activation in some frontal and posterior regions (anterior cingulate cortex [ACC], medial frontal gyrus, cuneus, precuneus, superior parietal lobule; F1,189=19.04–28.51, ps<.001, ηp2=.09-.13). Specifically, higher irritability was more strongly related to increased activation in younger relative to older youths. Conclusions: Following frustration, levels of irritability correlate with activity in neural systems mediating attention orienting, top-down regulation of emotions, and motor execution. While most associations were independent of age, dysfunction in ACC and posterior regions was more pronounced in young children with irritability.

A growing body of research has revealed that labeling an emotion, or putting one's feelings into words, can help to downregulate that affect, as occurs with intentional forms of emotion regulation, such as reappraisal and distraction. We translated this basic research to a real-world clinical context, in which spider-fearful individuals were repeatedly exposed to a live spider. Using a between-subjects design, we compared the effects of affect labeling, reappraisal, distraction from the feared stimulus, and exposure alone during this brief course of exposure therapy on subsequent fear responding. At a 1-week posttest involving a different spider in another context, the affect-labeling group exhibited reduced skin conductance response relative to the other groups and marginally greater approach behavior than the distraction group; however, the affect-labeling group did not differ from the other groups in self-reported fear. Additionally, greater use of anxiety and fear words during exposure was associated with greater reductions in fear responding. Thus, perhaps surprisingly, affect labeling may help to regulate aspects of emotion in a clinical context.

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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.