Estimating Multimodal Brain Variability in Schizophrenia Spectrum Disorders: A Worldwide ENIGMA Study

Objective Schizophrenia is a multifaceted disorder associated with structural brain heterogeneity. Despite its relevance for identifying illness subtypes and informative biomarkers, structural brain heterogeneity in schizophrenia remains incompletely understood. Therefore, the objective of this study was to provide a comprehensive insight into the structural brain heterogeneity associated with schizophrenia.Methods This meta- and mega-analysis investigated the variability of multimodal structural brain measures of white and gray matter in individuals with schizophrenia versus healthy controls. Using the ENIGMA dataset of MRI-based brain measures from 22 international sites with up to 6139 individuals for a given brain measure, we examined variability in cortical thickness, surface area, folding index, subcortical volume and fractional anisotropy.Results We found that individuals with schizophrenia are distinguished by higher heterogeneity in the frontotemporal network with regard to multimodal structural measures. Moreover, individuals with schizophrenia showed higher homogeneity of the folding index, especially in the left parahippocampal region.Conclusions Higher multimodal heterogeneity in frontotemporal regions potentially implies different subtypes of schizophrenia that converge on impaired frontotemporal interaction as a core feature of the disorder. Conversely, more homogeneous folding patterns in the left parahippocampal region might signify a consistent characteristic of schizophrenia shared across subtypes. These findings underscore the importance of structural brain variability in advancing our neurobiological understanding of schizophrenia, and aid in identifying illness subtypes as well as informative biomarkers.### Competing Interest StatementO. A. Andreassen: Consultant to Cortechs.ai, speakers honoraria from Lundbeck, Janssen, Sunovion. E. Seifritz received in the last four years honoraria and grants for advice and educational lectures from Lundbeck Switzerland, Schwabe Switzerland and Germany, Janssen Switzerland, Otsuka Pharmaceutical Switzerland, Mepha Pharma Switzerland, Recordati Switzerland and Sunovion Pharma United Kingdom and Angelini. P. Homan has received grants and honoraria from Novartis, Lundbeck, Mepha, Janssen, Boehringer Ingelheim, Neurolite outside of this work. No further disclosures were reported.