Specific Symptom Profiles are Associated with Distinct Changes in Amygdala Connectivity in Youth

Complex clinical presentations are common in youth seeking mental health treatment, complicating attempts to identify specific biological underpinnings to guide precision psychiatry. We defined four classes of such youth based on their symptom profiles and identified unique patterns of amygdala functional connectivity in each class. Subjects were 215 youth who varied along major symptom dimensions commonly associated with pediatric affective psychopathology: depression, irritability, anxiety, and attention-deficit/hyperactivity (ADHD). We used latent profile analysis to identify classes of symptom patterns. Functional MRI data were obtained while subjects completed a gender identification task of face-emotions that varied in emotion type and intensity. We used generalized psychophysiological interaction analysis to examine associations between the probability of being in each symptom class and amygdala functional connectivity. The likelihood of being in the class with high parent-reported irritability and ADHD symptoms was associated with amygdala connectivity to the insula and superior temporal gyrus while processing high-intensity angry and fearful faces; to the precuneus while processing intensity across emotions; and to the ventrolateral prefrontal cortex across all task conditions. The likelihood of being in the class with high anxious and depressive symptoms was negatively associated with amygdala-thalamic connectivity across task conditions. This is the first study to identify distinct associations between symptom profile classes and amygdala connectivity in a transdiagnostic sample of youth. These neural correlates provide external validity to latent classes derived from symptom clusters. This is an essential first step toward identifying the biological basis of common transdiagnostic symptom presentations in youth.