Three Cerebellar Imaging Subtypes in Schizophrenia with Distinct Spatiotemporal Trajectories and Biological Characteristics
Authors
Affiliations (1)
Affiliations (1)
- School of Biomedical Engineering, Shenzhen University Medical School, Shenzhen, PR China
Abstract
The potential role of the cerebellum in the pathophysiology of schizophrenia has received relatively insufficient attention. Prior studies characterized cerebellar abnormalities mainly at the group level, without fully considering the heterogeneity of the disease. Here, we applied a machine learning approach (Subtype and Stage Inference, SuStaIn) to cross-sectional 3D volumetric MRIs of the cerebellum, including a total of 3,550 individuals with schizophrenia (1423 females; mean age: 32.3 {+/-} 12.0 years) and 5,771 healthy controls (HC) (2,861 females; mean age: 32.5 {+/-} 12.9 years), from 34 sites worldwide. SuStaIn identified three distinct spatiotemporal trajectories in cerebellar gray matter volume reduction, respectively originating in lobule X (subtype 1), lobule III (subtype 2) and lobule VIIb (subtype 3), with subtypes 1 and 3 corresponding to the posterior lobe and subtype 2 to the anterior lobe. These trajectories were cross-sectionally inferred in 1,588 individuals with schizophrenia and replicated in another independent samples of 1,334 and 628 patients, respectively. Multimodal analyses using neuroimaging, transcriptomic and behavioral data revealed subtype-specific biological characteristics in brain morphological patterns, cerebellar-cortical connectivity, gene expression and clinical symptoms. Specifically, subtype-related genes were enriched in metabolism-related processes and immunity-related processes, respectively, in subtype 1 and subtype 2; subtype 3 showed more severe brain abnormalities and worse cognitive symptoms. Treatment data from 381 patients, with up to 12 months of follow-up, revealed poorer response to antipsychotic medications in subtype 2 and subtype 3, but better response to transcranial magnetic stimulation in subtype 1, which also had worse emotion-related symptoms. Together, our findings offer a comprehensive characterization of the heterogeneity of cerebellar pathophysiological progresses in schizophrenia, which may help in developing future clinical stratification and targeted intervention strategies.