Cerebellar grey matter volume in adolescence is associated with prodromal psychotic symptoms and norm-violating behavior

Importance: Accumulating evidence supports cerebellar involvement in mental disorders such as schizophrenia, bipolar disorder, depression, anxiety disorders and attention-deficit hyperactivity disorder. However, little is known about cerebellar involvement in the developmental stages of these disorders. In particular, whether cerebellar morphology is associated with early expression of specific symptom domains remains unclear. Objective: To determine the robustness and specificity of associations between cerebellar morphology, general cognitive function, general psychopathology and sub-clinical psychiatric symptom domains in adolescence. Design, setting and participants: Assessment of parametric structure-function associations between MR-based brain morphometric features and data-driven cognitive and clinical phenotypes in the Philadelphia Neurodevelopmental Cohort (N=1401, age-range: 8 - 23). Main outcomes and measures: Robust prediction of cognitive and clinical symptom domain scores from cerebellar, subcortical and cerebro-cortical brain features using machine learning with 10-fold internal cross-validation and permutation-based statistical inference. Results: Cerebellar morphology predicted both general cognitive function and general psychopathology (mean Pearson correlation coefficients between predicted and observed values: r = .20 and r = .13, respectively; corrected p-values .1). Associations with norm-violating behavior and prodromal psychotic symptoms were stronger for the cerebellum than for subcortical and cerebro-cortical regions, while anxiety and general cognitive function were related to more global brain morphology patterns. The association between cerebellar volume and prodromal psychotic symptoms, and to a lesser extent norm violating behavior, remained significant when adjusting for potentially confounding factors such as general cognitive function, general psychopathology, parental education level and use of psychoactive substances. Conclusions and relevance: The robust associations with sub-clinical psychiatric symptoms in the age range when these typically emerge highlight the cerebellum as a key brain structure in the development of severe mental disorders.