The relationship between pathological brain activity and functional network connectivity in glioma patients
Authors: Zimmermann Mona LM , Breedt Lucas C , Centeno Eduarda GZ , Reijneveld Jaap C , Santos Fernando AN , Stam Cornelis J , van Lingen Marike R , Schoonheim Menno M , Hillebrand Arjan , Douw Linda 
Published: April 2023

AbstractBackgroundGlioma is associated with pathologically high peritumoral brain activity, which relates to faster progression. Functional connectivity is disturbed locally and throughout the entire brain, associating with symptomatology. We, therefore, investigated how local activity and network measures relate to better understand how the intricate relationship between the tumor and the rest of the brain may impact disease and symptom progression.MethodsWe obtained magnetoencephalography in 84de novoglioma patients and 61 matched healthy controls. The offset of the power spectrum, a proxy of neuronal activity, was calculated for 210 cortical regions. We calculated patients’ regional deviations in delta, theta and lower alpha network connectivity as compared to controls, using two network measures: clustering coefficient, a measure of local connectivity, and eigenvector centrality (integrative connectivity). We then tested group differences in activity and connectivity between peritumoral, contralateral homologue regions, and the rest of the brain. We also correlated regional offset to connectivity.ResultsAs expected, patients’ peritumoral activity was pathologically high, and patients showed higher clustering and lower centrality than controls. At the group-level, regionally high activity related to high clustering in controls and patients alike. However, within-patient analyses revealed negative associations between regional deviations in brain activity and clustering, such that pathologically high activity coincided with low network clustering, while regions with ‘normal’ activity levels showed high network clustering.ConclusionsOur results indicate that pathological activity and connectivity co-localize in a complex manner in glioma. This insight is relevant to our understanding of disease progression and cognitive symptomatology.KeypointsRegional activity and network clustering are pathologically high in gliomaHowever, high-activity regions show low clustering and vice versaThis finding could be relevant to understand functioning and prognosis in gliomaImportance of the studyGlioma patients show high peritumoral brain activity, which relates to faster tumor progression. Moreover, patients have local and global functional network disturbances, which associate with cognitive dysfunction and other symptoms. However, how such activity and network deviations correlate across and within patients is unclear. We, therefore, studied a large cohort of newly diagnosed glioma patients and matched healthy controls, extracting activity and connectivity from the entire cortex. We find a surprising relationship between deviations in activity and local clustering: while higher activity and clustering go hand in hand in controls, the pathologically high activity we observe in individual glioma patients coincides with exceedingly low clustering, while areas with normal activity levels have pathologically high clustering. These insights indicate an intricate relationship between aberrant activity and connectivity throughout the brain in glioma. It remains to be seen how this complex relationship impacts tumor growth and potentially cognitive deficits.