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.