Neurodevelopmental risk and adaptation as a model for comorbidity among internalizing and externalizing disorders: genomics and cell-specific expression enriched morphometric study.

BACKGROUND: Comorbidity is the rule rather than the exception for childhood and adolescent onset mental disorders, but we cannot predict its occurrence and do not know the neural mechanisms underlying comorbidity. We investigate if the effects of comorbid internalizing and externalizing disorders on anatomical differences represent a simple aggregate of the effects on each disorder and if these comorbidity-associated cortical surface differences relate to a distinct genetic underpinning. METHODS: We studied the cortical surface area (SA) and thickness (CT) of 11,878 preadolescents (9-10 years) from the Adolescent Brain and Cognitive Development Study. Linear mixed models were implemented in comparative and association analyses among internalizing (dysthymia, major depressive disorder, disruptive mood dysregulation disorder, agoraphobia, panic disorder, specific phobia, separation anxiety disorder, social anxiety disorder, generalized anxiety disorder, post-traumatic stress disorder), externalizing (attention-deficit/hyperactivity disorder, oppositional defiant disorder, conduct disorder) diagnostic groups, a group with comorbidity of the two and a healthy control group. Genome-wide association analysis (GWAS) and cell type specificity analysis were performed on 4468 unrelated European participants from this cohort. RESULTS: Smaller cortical surface area but higher thickness was noted across patient groups when compared to controls. Children with comorbid internalizing and externalizing disorders had more pronounced areal reduction than those without comorbidity, indicating an additive burden. In contrast, cortical thickness had a non-linear effect with comorbidity: the comorbid group had no significant CT differences, while those patient groups without comorbidity had significantly higher thickness compare to healthy controls. Distinct biological pathways were implicated in regional SA and CT differences. Specifically, CT differences were associated with immune-related processes implicating astrocytes and oligodendrocytes, while SA-related differences related mainly to inhibitory neurons. CONCLUSION: The emergence of comorbidity across distinct clusters of psychopathology is unlikely to be due to a simple additive neurobiological effect alone. Distinct developmental risk moderated by immune-related adaptation processes, with unique genetic and cell-specific factors, may contribute to underlying SA and CT differences. Children with the highest risk but lowest resilience, both captured in their developmental morphometry, may develop a comorbid illness pattern.

Decoding anxiety-impulsivity subtypes in preadolescent internalising disorders: findings from the Adolescent Brain Cognitive Development study.

BACKGROUND: Internalising disorders are highly prevalent emotional dysregulations during preadolescence but clinical decision-making is hampered by high heterogeneity. During this period impulsivity represents a major risk factor for psychopathological trajectories and may act on this heterogeneity given the controversial anxiety-impulsivity relationships. However, how impulsivity contributes to the heterogeneous symptomatology, neurobiology, neurocognition and clinical trajectories in preadolescent internalising disorders remains unclear. AIMS: The aim was to determine impulsivity-dependent subtypes in preadolescent internalising disorders that demonstrate distinct anxiety-impulsivity relationships, neurobiological, genetic, cognitive and clinical trajectory signatures. METHOD: We applied a data-driven strategy to determine impulsivity-related subtypes in 2430 preadolescents with internalising disorders from the Adolescent Brain Cognitive Development study. Cross-sectional and longitudinal analyses were employed to examine subtype-specific signatures of the anxiety-impulsivity relationship, brain morphology, cognition and clinical trajectory from age 10 to 12 years. RESULTS: We identified two distinct subtypes of patients who internalise with comparably high anxiety yet distinguishable levels of impulsivity, i.e. enhanced (subtype 1) or decreased (subtype 2) compared with control participants. The two subtypes exhibited opposing anxiety-impulsivity relationships: higher anxiety at baseline was associated with higher lack of perseverance in subtype 1 but lower sensation seeking in subtype 2 at baseline/follow-up. Subtype 1 demonstrated thicker prefrontal and temporal cortices, and genes enriched in immune-related diseases and glutamatergic and GABAergic neurons. Subtype 1 exhibited cognitive deficits and a detrimental trajectory characterised by increasing emotional/behavioural dysregulations and suicide risks during follow-up. CONCLUSIONS: Our results indicate impulsivity-dependent subtypes in preadolescent internalising disorders and unify past controversies about the anxiety-impulsivity interaction. Clinically, individuals with a high-impulsivity subtype exhibit a detrimental trajectory, thus early interventions are warranted.

Common and disorder-specific cortical thickness alterations in internalizing, externalizing and thought disorders during early adolescence: an Adolescent Brain and Cognitive Development study.

BACKGROUND: A growing body of neuroimaging studies has reported common neural abnormalities among mental disorders in adults. However, it is unclear whether the distinct disorder-specific mechanisms operate during adolescence despite the overlap among disorders. METHODS: We studied a large cohort of more than 11 000 preadolescent (age 9-10 yr) children from the Adolescent Brain and Cognitive Development cohort. We adopted a regrouping approach to compare cortical thickness (CT) alterations and longitudinal changes between healthy controls (n = 4041) and externalizing (n = 1182), internalizing (n = 1959) and thought disorder (n = 347) groups. Genome-wide association study (GWAS) was performed on regional CT across 4468 unrelated European youth. RESULTS: Youth with externalizing or internalizing disorders exhibited increased regional CT compared with controls. Externalizing (p = 8 × 10-4, Cohen d = 0.10) and internalizing disorders (p = 2 × 10-3, Cohen d = 0.08) shared thicker CT in the left pars opercularis. The somatosensory and the primary auditory cortex were uniquely affected in externalizing disorders, whereas the primary motor cortex and higher-order visual association areas were uniquely affected in internalizing disorders. Only youth with externalizing disorders showed decelerated cortical thinning from age 10-12 years. The GWAS found 59 genome-wide significant associated genetic variants across these regions. Cortical thickness in common regions was associated with glutamatergic neurons, while internalizing-specific regional CT was associated with astrocytes, oligodendrocyte progenitor cells and GABAergic neurons. LIMITATIONS: The sample size of the GWAS was relatively small. CONCLUSION: Our study provides strong evidence for the presence of specificity in CT, developmental trajectories and underlying genetic underpinnings among externalizing and internalizing disorders during early adolescence. Our results support the neurobiological validity of the regrouping approach that could supplement the use of a dimensional approach in future clinical practice.