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Original Investigation
June 2018

A Latent Variable Approach to Differentiating Neural Mechanisms of Irritability and Anxiety in Youth

Author Affiliations
  • 1Emotion and Development Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland
  • 2Department of Child and Adolescent Psychiatry and Behavioral Sciences, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
  • 3Department of Psychology, San Diego State University, San Diego, California
  • 4Joint Doctoral Program in Clinical Psychology, San Diego State University, San Diego, California
  • 5University of California, San Diego, San Diego
JAMA Psychiatry. 2018;75(6):631-639. doi:10.1001/jamapsychiatry.2018.0468
Key Points

Question  Can latent variable statistical methods differentiate neural mechanisms of co-occurring symptom dimensions in youth?

Findings  In this magnetic resonance imaging study of 197 youth aged 8 to 18 years, bifactor analysis decomposed the unique and shared variances of irritability and anxiety symptoms. On a functional neuroimaging task assessing threat orienting, these phenotypes showed a double dissociation: irritability was associated with widespread perturbed neural activation, whereas anxiety was associated with perturbed amygdala connectivity.

Meaning  A bifactor approach to modeling pediatric psychopathology revealed a novel double dissociation in which phenotype-specific mechanisms were found to underlie clinically relevant threat orienting.


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.