Neurodevelopmental risk and adaptation as a model for comorbidity among internalizing and externalizing disorders:...

Area of Science:

• Neuroscience
• Developmental Psychology
• Genetics

Background:

• Comorbidity in childhood and adolescent mental disorders is common but poorly understood.
• Neural mechanisms underlying comorbidity remain unclear.
• Predicting comorbidity occurrence is a significant challenge.

Purpose of the Study:

• To investigate if comorbid internalizing and externalizing disorders have an additive effect on cortical anatomical differences.
• To determine if comorbidity-associated cortical differences have a distinct genetic basis.

Main Methods:

• Analysis of cortical surface area (SA) and thickness (CT) in 11,878 preadolescents (9-10 years) from the Adolescent Brain and Cognitive Development Study.
• Use of linear mixed models for comparative and association analyses across diagnostic groups (internalizing, externalizing, comorbid, healthy controls).
• Genome-wide association analysis (GWAS) and cell type specificity analysis on 4468 unrelated European participants.

Main Results:

• Patient groups showed smaller cortical SA and higher CT compared to controls.
• Comorbid internalizing and externalizing disorders exhibited more pronounced SA reduction (additive effect).
• Cortical thickness showed a non-linear effect: comorbid group had no significant CT differences, while non-comorbid patients had higher CT than controls.
• Distinct biological pathways implicated: CT differences linked to immune processes (astrocytes, oligodendrocytes), SA differences linked to inhibitory neurons.

Conclusions:

• Comorbidity in psychopathology is unlikely solely due to additive neurobiological effects.
• Distinct developmental risks, immune-related adaptations, and unique genetic/cell-specific factors contribute to SA and CT differences.
• Children with high risk and low resilience, reflected in brain morphometry, may develop comorbid illness patterns.