Latent Variable Approach Effective in Parsing Neural Mechanisms of Co-Occurring Anxiety, Irritability in Youth

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These results indicate that a "latent variable" approach may be useful for neuropsychiatric research involving co-occurring symptoms.

According to data published in JAMA Psychiatry, pediatric irritability and anxiety had unique influences on threat orientation in youth: during orientation away from threat, irritability alone was associated with neural activity, whereas anxiety was associated with amygdala connectivity. The ability of researchers to parse specific symptom dimensions from typically co-occurring conditions supports the efficacy of a latent variable approach for clinical neuroscience studies.  

Researchers performed a cross-sectional functional magnetic resonance imaging (MRI) study that included 197 participants aged 8 to 18 years who had received diagnoses spanning multiple diagnostic categories. Of these, 141 participants had disruptive mood dysregulation disorder, anxiety disorder, and/or attention-deficit/hyperactivity disorder, and 56 participants served as healthy controls. 

The mean (standard deviation) age of the cohort was 13.1 (2.7) years, and 91 (46.2%) participants were girls. Irritability and anxiety in the participants were captured using the Affective Reactivity Index and the Screen for Child Anxiety Related Emotional Disorders, respectively. A functional MRI dot-probe task was used to assess attention orienting to angry (ie, threat) faces compared with neutral faces. Neural activity and amygdala functional connectivity were examined by means of whole-brain analyses.

A best-fit bifactor analysis quantified the shared variances of irritability and anxiety symptoms and included 4 factors: parent-reported irritability, youth-reported irritability, anxiety (both parent and youth reported), and a common factor termed “negative affectivity” by investigators. During orientation away from threat, higher parent-reported irritability was associated with increased neural activity in the insula, caudate, dorsolateral and ventrolateral prefrontal cortex, and inferior parietal lobule (P <.001 for all). Under identical circumstances, higher anxiety was associated with decreased amygdala connectivity with the cingulated, thalamus, and precentral gyrus (P <.001 for all). Using their bifactor model, researchers were able to parse the phenotypic-specific brain mechanisms involved in threat orienting despite the frequent co-occurrence of irritability and anxiety. These results indicate that a “latent variable” approach may be useful for neuropsychiatric research involving co-occurring symptoms.

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The cross-sectional study design may limit data generalizability, and investigators suggested that future studies should include additional diagnostic groups, including unipolar and bipolar depression. In addition to continued monitoring of the mechanisms of anxiety and irritability, further identification of certain psychiatric disease biomarkers may be helpful in developing effective treatments for children and adolescents. 


Kircanski K, White LK, Tseng W-L, et al. A latent variable approach to differentiating neural mechanisms of irritability and anxiety in youth [published online April 6, 2018]. JAMA Psychiatry. doi:10.1001/jamapsychiatry.2018.0468