Structural network embedding governs peritumor and distant pathological brain activity in glioblastoma

Glioblastomas integrate into the brain globally, where they provoke neuronal hyperactivity to enhance tumor growth and invasion. Communication of glioblastomas with neurons is not only present locally, but has preclinically been shown to extend towards the contralateral hemisphere through white matter tracts. However, it remains unknown how the distant hyperactivity that is often found in patients relates to structural embedding of the tumor into the larger brain network. 29 newly diagnosed IDH-wildtype glioblastoma patients and 25 age and sex matched healthy controls were included. To define structural tumor embedding, we overlayed each patient-specific tumor mask with a normative structural connectome obtained from diffusion MRI. We identified the average number of streamlines intersecting the tumor, extracting the tumors average tract density ( Lesion-Tract Density Index, L-TDI). For a subgroup of patients (n = 17), we determined structural embedding directly from diffusion scans and subsequent tractography. To identify regions connecting to the tumor, we seeded from each patients tumor rim outside FLAIR hyperintensities in the white matter to the 210 cortical regions of the Brainnetome atlas. We then counted the number of tumor-connecting regions, termed PATNET hereafter. Finally, participants underwent eyes-closed resting-state magnetoencephalography. We used broadband power as a proxy for neuronal spiking activity of each cortical region. To capture deviant brain activity in tumor and non-tumor regions, we regionally standardized broadband values using controls. We then sought to establish an association of deviant peritumor activity with both L-TDI and PATNET. Subsequently, we investigated whether tumor-connected regions showed more deviant activity than unconnected regions. Finally, we explored the clinical relevance of L-TDI and PATNET. Greater structural tumor embedding significantly related to more deviant peritumor activity (rhoLTDI= 0.47, PLTDI = .010; rhoPATNET = 0.54, PPATNET = .024), with larger tumors showing greater embedding and more hyperactivity than smaller tumors. Furthermore, distant tumor-connected regions showed more hyperactivity than unconnected regions, but only in patients with peritumor hyperactivity (F(1,15) = 11.02, P =.005). Finally, higher PATNET associated with lower KPS (U = 61.5, P = .015). Glioblastomas structural embedding explains hyperactivity around the tumor and in distant cortical regions, such that distant hyperactivity occurs primarily when there is tumor hyperactivity and the region is structurally connected to the tumor. Moreover, patient-specific tumor embedding relates to functional status.