Gliomas preferentially develop within the action-mode network

Abstract Gliomas tend to arise in specific brain regions and may integrate into functional circuits, suggesting they could be regulated by brain activity. However, it remains unclear whether glioma growth is related to system-level brain networks. Analyzing neuroimaging data from three datasets including 1,310 patients with cerebral gliomas, we identified and replicated a functionally connected glioma network, which overlaps with the action-mode network (AMN), somatomotor network (SMN), and action-related subcortical regions. Resting-state functional connectivity (RSFC) of the AMN successfully predicted the location of glioma occurrence in two independent datasets with complex tumor distributions. Remarkably, no patient had a glioma entirely outside the AMN, and over 89% of patients exhibited gliomas with at least 50% overlap with the network. Moreover, the spatial overlap between glioma location and the AMN demonstrated significant prognostic value in survival analyses, with higher AMN-tumor overlap associated with poorer overall survival. Notably, the acetylcholine transporter, a key player in glioma pathogenesis that drives transcriptional reprogramming, showed an expression pattern overlapping with the AMN. Meta-analytic annotations further linked the glioma network to processes of action initiation, execution, and feedback. These findings indicate that gliomas preferentially arise in circuits involved in action and highlight the central role of the AMN in glioma pathophysiology and growth. Competing Interest Statement H.L. is the chief scientist of Neural Galaxy Inc. N.U.F.D. has a financial interest in Turing Medical Inc. and may financially benefit if the company is successful in marketing FIRMM motion monitoring software products. E.M.G. and N.U.F.D. may receive royalty income based on FIRMM technology developed at Washington University School of Medicine and licensed to Turing Medical Inc. N.U.F.D. is a co-founder of Turing Medical Inc. These potential conflicts of interest have been reviewed and are managed by Washington University School of Medicine. Other authors declare no conflict of interest regarding the publication of this work. Footnotes The order of the author name has been corrected.