Although cerebellar involvement across a wide range of cognitive and neuropsychiatric phenotypes is increasingly being recognized, previous large-scale studies in schizophrenia (SZ) have primarily focused on supratentorial structures. Hence, the across-sample reproducibility, regional distribution, associations with cerebrocortical morphology and effect sizes of cerebellar relative to cerebral morphological differences in SZ are unknown. We addressed these questions in 983 patients with SZ spectrum disorders and 1349 healthy controls (HCs) from 14 international samples, using state-of-the-art image analysis pipelines optimized for both the cerebellum and the cerebrum. Results showed that total cerebellar grey matter volume was robustly reduced in SZ relative to HCs (Cohens’s d=−0.35), with the strongest effects in cerebellar regions showing functional connectivity with frontoparietal cortices (d=−0.40). Effect sizes for cerebellar volumes were similar to the most consistently reported cerebral structural changes in SZ (e.g., hippocampus volume and frontotemporal cortical thickness), and were highly consistent across samples. Within groups, we further observed positive correlations between cerebellar volume and cerebral cortical thickness in frontotemporal regions (i.e., overlapping with areas that also showed reductions in SZ). This cerebellocerebral structural covariance was strongest in SZ, suggesting common underlying disease processes jointly affecting the cerebellum and the cerebrum. Finally, cerebellar volume reduction in SZ was highly consistent across the included age span (16–66 years) and present already in the youngest patients, a finding that is more consistent with neurodevelopmental than neurodegenerative etiology. Taken together, these novel findings establish the cerebellum as a key node in the distributed brain networks underlying SZ.
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We thank the participants of the study for their contribution, and the clinicians who were involved in patient recruitment and clinical assessments. The study has received funding from the European Commission’s 7th Framework Programme (No. 602450, IMAGEMEND), Research Council of Norway (213837, 223273, 204966/F20, 249795/F20), the South-Eastern Norway Regional Health Authority (2013-123, 2014-097, 2015-073, 2016-083) and KG Jebsen Foundation. Data used in preparation of this article were obtained from the SchizConnect (http://schizconnect.org) and OpenfMRI (http://openfmri.org) databases. As such, the investigators within SchizConnect and OpenfMRI contributed to the design and implementation of SchizConnect/OpenfMRI and/or provided data but did not participate in analysis or writing of this report. The respective SchizConnect/OpenfMRI samples were supported by the following grants: NIH Grants 5P20RR021938 and P20GM103472 (COBRE), NIMH Grant 1R01 MH084803 (NÙSDAST), Department of Energy Award Number DE-FG02-08ER64581 (MCIC), NIH Roadmap for Medical Research Grants UL1-DE019580, RL1MH083268, RL1MH083269, RL1DA024853, RL1MH083270, RL1LM009833, PL1MH083271 and PL1NS062410 (CNP), NIH Grants P50 MH071616 and R01 MH56584 (CCNMD).
The authors declare no conflict of interest.
MEMBERS OF THE KAROLINSKA SCHIZOPHRENIA PROJECT (KaSP): COLLABORATORS Drs Flyckt, Fatouros-Bergman, and Agartz are members of KASP. The other members are L Farde1, G Engberg2, S Erhardt2, S Cervenka1, L Schwieler2, F Piehl3, P Ikonen1, K Collste1, F Orhan2, A Malmqvist1 and M Hedberg1. 1Center for Psychiatric Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; 2Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden; 3Neuroimmunology Unit, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
Supplementary Information accompanies the paper on the Molecular Psychiatry website
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Moberget, T., Doan, N., Alnæs, D. et al. Cerebellar volume and cerebellocerebral structural covariance in schizophrenia: a multisite mega-analysis of 983 patients and 1349 healthy controls. Mol Psychiatry 23, 1512–1520 (2018). https://doi.org/10.1038/mp.2017.106
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