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

Abstract

ImportanceAccumulating 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.\n\nObjectiveTo determine the robustness and specificity of associations between cerebellar morphology, general cognitive function, general psychopathology and sub-clinical psychiatric symptom domains in adolescence.\n\nDesign, setting and participantsAssessment 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).\n\nMain outcomes and measuresRobust 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.\n\nResultsCerebellar 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 < .0009). Analyses of specific sub-clinical symptom domains revealed significant associations with rates of norm-violating behavior (r = .17; p < .0009), prodromal psychotic symptoms (r = .12; p < .0009) and anxiety symptoms (r = .09; p =.0117). In contrast, we observed no significant associations between cerebellar features and the severity of attention deficits, depressive, manic or obsessive-compulsive symptoms (all rs =< .03, all ps => .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.\n\nConclusions and relevanceThe 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.\n\nKey pointsO_ST_ABSQuestionsC_ST_ABSIs cerebellar morphology associated with sub-clinical psychiatric symptoms in adolescence? Do such associations show symptom domain specificity or do they rather constitute a marker of general psychopathology?\n\nFindingsMachine learning utilizing cerebellar morphology features significantly predicted the severity of prodromal psychotic symptoms, norm-violating behavior and anxiety, but not attention deficits, depressive, manic or obsessive-compulsive sub-clinical symptoms. Associations with prodromal psychotic symptoms were stronger for the cerebellum than for cerebral subcortical and cerebro-cortical regions, and remained significant when adjusting for several potentially confounding factors.\n\nMeaningThe cerebellum appears to play a key role in the development of severe mental illness.