Regional healthy brain activity, glioma occurrence and symptomatology
Authors: Numan Tianne , Breedt Lucas C. , Maciel Bernardo de A.P.C. , Kulik Shanna D. , Derks Jolanda , Schoonheim Menno M. , Klein Martin , de Witt Hamer Philip C. , Miller Julie J. , Gerstner Elizabeth R. , Stufflebeam Steven M. , Hillebrand Arjan , Stam Cornelis J. , Geurts Jeroen J.G. , Reijneveld Jaap C. , Douw Linda 
Published: January 2022

It is unclear why exactly gliomas show preferential occurrence in certain brain areas. Increased spiking activity around gliomas leads to faster tumor growth in animal models, while higher non-invasively measured brain activity is related to shorter survival in patients. However, it is unknown how regional intrinsic brain activity, as measured in healthy controls, relates to glioma occurrence. We first investigated whether gliomas occur more frequently in regions with intrinsically higher brain activity. Secondly, we explored whether intrinsic cortical activity at individual patients’ tumor locations relates to tumor and patient characteristics.

Across three cross-sectional cohorts, 306 patients with different tumor subtypes were included. Tumor masks were created for each patient. Intrinsic regional brain activity was assessed through resting-state magnetoencephalography (MEG) acquired in healthy controls, which was then source-localized to 210 cortical brain regions according to the Brainnetome atlas. Brain activity was operationalized as (1) broadband power and (2) offset of the aperiodic component of the power spectrum, which both reflect neuronal spiking of the underlying neuronal population. We additionally assessed (3) the slope of the aperiodic component of the power spectrum, which is thought to reflect the neuronal excitation/inhibition (E/I) balance. First, correlation coefficients were calculated between group-level regional glioma occurrence, as obtained by concatenating tumor masks across patients, and group-averaged regional intrinsic brain activity. Second, intrinsic brain activity at specific tumor locations was calculated by overlaying patients’ individual tumor masks with regional intrinsic brain activity of the controls and was associated with tumor and patient characteristics.

As hypothesized, more malignant glioma preferentially occurred in brain regions characterized by higher intrinsic brain activity in controls as reflected by higher offset. Secondly, intrinsic brain activity at patients’ individual tumor locations differed according to glioma subtype and performance status: the most malignant IDH-wildtype glioblastoma patients had the lowest E/I balance at their individual tumor locations, while lower E/I balance weakly related to poorer Karnofsky performance status, independent of glioma subtype.

In conclusion, malignant gliomas more frequently occur in cortical brain regions with intrinsically higher activity levels, suggesting that more active regions are more vulnerable to glioma development. Moreover, indices of healthy, intrinsic E/I balance at patients’ individual tumor locations may capture both tumor biology and patients’ performance status. These findings contribute to our understanding of the complex and bidirectional relationship between normal brain functioning and glioma growth, which is at the core of the relatively new field of ‘cancer neuroscience’.