Three Cerebellar Imaging Subtypes in Schizophrenia with Distinct Spatiotemporal Trajectories and Biological Characteristics
Year: 2026
Type: preprint
Study design: Observational Study
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.
Source: medRxiv
Authors: Zhaoyun Liu, Zhenyu Huang, Xinjia Lin, Jingyu Zhou, Hao Hu, Qian Guo, Yingying Tang, Tianhong Zhang, Jijun Wang, Weihua Yue, Yuyanan Zhang, Xin Yu, Long-Biao Cui, Xiao Chang, Huan Huang, Cheng Luo, Dezhong Yao, Ryota Hashimoto, Junya Matsumoto, Kiyotaka Nemoto, Tilo Kircher, Florian Thomas-Odenthal, Paula Usemann, Lea Teutenberg, Benjamin Straube, Igor Nenadić, Frederike Stein, Nina Alexander, Andreas Jansen, Hamidreza Jamalabadi, Nooshin Javaheripour, Jannik Lepper, Udo Dannlowski, Dominik Grotegerd, Susanne Meinert, Kira Flinkenflugel, Rebekka Lencer, Michael Ziller, Edith Pomarol-Clotet, Raymond Salvador, Andriana Karuk, Gianfranco Spalletta, Fabrizio Piras, Daniela Vecchio, Nerisa Banaj, Ali Saffet Gonul, Asli Ceren Hinc, Kang Sim, Qian Hui Chew, Yann Quidé, Melissa J. Green, Young-Chul chung, Woo-Sung Kim, Soyolsaikhan Odkhuu, Felice Iasevoli, Giuseppe Pontillo, Andrea de Bartolomeis, Sirio Cocozza, Annarita Barone, Arturo Brunetti, Mariateresa Ciccarelli, Mario Tranfa, Tamsyn E.Van Rheenen, Susan L Rossell, Matthew Hughes, Will Woods, Sean Carruthers, Philip J. Sumner, Elysha Ringin, Georgia Caruana, Scott R. Sponheim, Jessica A. Turner, Theo G.M. van Erp, Lena Palaniyappan, Paul M. Thompson, Jianfeng Feng, Yuchao Jiang
Institutions: Shenzhen University, Shanghai Jiao Tong University, Shanghai Mental Health Center, Shanghai Key Laboratory of Psychotic Disorders, Peking University Sixth Hospital, Air Force Medical University, Fudan University, University of Electronic Science and Technology of China, National Center of Neurology and Psychiatry, National Institute of Mental Health, National Center Hospital of Neurology and Psychiatry, University of Tsukuba, Philipps University of Marburg, Bielefeld University, University of Münster, Fidmag Sisters Hospitallers, Fondazione Santa Lucia, Ege University, Institute of Mental Health, UNSW Sydney, Neuroscience Research Australia, Jeonbuk National University, University of Naples Federico II, Federico II University Hospital, The University of Melbourne, Swinburne University of Technology, Minneapolis VA Medical Center, The Ohio State University Wexner Medical Center, University of California, Irvine, Douglas Mental Health University Institute, McGill University, University of Southern California
Language: English
Subfield: Psychiatry and Mental health
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7220438504