Three Cerebellar Imaging Subtypes in Schizophrenia with Distinct Spatiotemporal Trajectories and Biological Characteristics
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.
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BibTeX
@misc{liu2026three,
title = {{Three Cerebellar Imaging Subtypes in Schizophrenia with Distinct Spatiotemporal Trajectories and Biological Characteristics}},
author = {Z. Liu and Z. Huang and X. Lin and J. Zhou and H. Hu and Q. Guo and Y. Tang and T. Zhang and J. Wang and W. Yue and Y. Zhang and X. Yu and L.-B. Cui and X. Chang and H. Huang and C. Luo and D. Yao and R. Hashimoto and J. Matsumoto and K. Nemoto and T. Kircher and F. Thomas-Odenthal and P. Usemann and L. Teutenberg and B. Straube and I. Nenadic and F. Stein and N. Alexander and A. Jansen and H. Jamalabadi and N. Javaheripour and J. Lepper and U. Dannlowski and D. Grotegerd and S. Meinert and K. Flinkenflugel and R. Lencer and M. Ziller and A. S. Gonul and A. C. Hinc and K. Sim and Q. H. Chew and Y. Quide and M. J. Green and Y.-C. chung and W.-S. Kim and S. Odkhuu and F. Iasevoli and Ponti},
howpublished = {medRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.03.26364634},
url = {https://www.medrxiv.org/content/10.64898/2026.10.03.26364634v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Three Cerebellar Imaging Subtypes in Schizophrenia with Distinct Spatiotemporal Trajectories and Biological Characteristics
AU - Z. Liu
AU - Z. Huang
AU - X. Lin
AU - J. Zhou
AU - H. Hu
AU - Q. Guo
AU - Y. Tang
AU - T. Zhang
AU - J. Wang
AU - W. Yue
AU - Y. Zhang
AU - X. Yu
AU - L.-B. Cui
AU - X. Chang
AU - H. Huang
AU - C. Luo
AU - D. Yao
AU - R. Hashimoto
AU - J. Matsumoto
AU - K. Nemoto
AU - T. Kircher
AU - F. Thomas-Odenthal
AU - P. Usemann
AU - L. Teutenberg
AU - B. Straube
AU - I. Nenadic
AU - F. Stein
AU - N. Alexander
AU - A. Jansen
AU - H. Jamalabadi
AU - N. Javaheripour
AU - J. Lepper
AU - U. Dannlowski
AU - D. Grotegerd
AU - S. Meinert
AU - K. Flinkenflugel
AU - R. Lencer
AU - M. Ziller
AU - A. S. Gonul
AU - A. C. Hinc
AU - K. Sim
AU - Q. H. Chew
AU - Y. Quide
AU - M. J. Green
AU - Y.-C. chung
AU - W.-S. Kim
AU - S. Odkhuu
AU - F. Iasevoli
AU - Ponti
PY - 2026
DA - 2026/10/03
PB - medRxiv
DO - 10.64898/2026.10.03.26364634
UR - https://www.medrxiv.org/content/10.64898/2026.10.03.26364634v1
AB - 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.
ER -