Resting-state fMRI detects alterations in whole brain connectivity related to tumor biology in glioma patients

Abstract

Background Systemic infiltration of the brain by tumor cells is a hallmark of glioma pathogenesis which may cause disturbances in functional connectivity. We hypothesized that aggressive high-grade tumors cause more damage to functional connectivity than low-grade tumors. Methods We designed an imaging tool based on resting-state functional (f)MRI to individually quantify abnormality of functional connectivity and tested it in a prospective cohort of patients with newly diagnosed glioma. Results Thirty-four patients were analyzed (World Health Organization [WHO] grade II, n = 13; grade III, n = 6; grade IV, n = 15; mean age, 48.7 y). Connectivity abnormality could be observed not only in the lesioned brain area but also in the contralateral hemisphere with a close correlation between connectivity abnormality and aggressiveness of the tumor as indicated by WHO grade. Isocitrate dehydrogenase 1 (IDH1) mutation status was also associated with abnormal connectivity, with more alterations in IDH1 wildtype tumors independent of tumor size. Finally, deficits in neuropsychological performance were correlated with connectivity abnormality. Conclusion Here, we suggested an individually applicable resting-state fMRI marker in glioma patients. Analysis of the functional connectome using this marker revealed that abnormalities of functional connectivity could be detected not only adjacent to the visible lesion but also in distant brain tissue, even in the contralesional hemisphere. These changes were associated with tumor biology and cognitive function. The ability of our novel method to capture tumor effects in nonlesional brain suggests a potential clinical value for both individualizing and monitoring glioma therapy.

Distributed changes of the functional connectome in patients with glioblastoma

“…Even though the exact mechanisms remain speculative, such a global impact might be due to forward-propagation of locally perturbed connections within one network (such as tumour-associated destruction and oedema) to hierarchically connected further networks. Of note, the global impact we observe is in line with recent work that also included tumour-bearing voxels in their analysis 15 . Our results corroborate recent studies which observed a shift in connectivity profiles in patients with newly diagnosed glioma 23 .…”

“…We found patterns of network alterations across all patients irrespective of tumour size or location. In all cases, focal lesions were associated with widespread and symmetric anomaly in both hemispheres in a network-specific manner across all seven resting-state networks in line with recent work 15 , 23 . In our study, network anomaly refers to the relative deviation from network connectivity of a control population and does not necessarily reflect increased or decreased activity.…”

“…Only recently, the global impact of brain tumours, even if circumscribed lesions, on brain networks has been acknowledged. For instance, higher alterations of the network structure were observed in high-grade as compared to low-grade gliomas 15 . Gliomas located in the left parietal cortex were found to be associated with widely reduced connectivity within the extended bilateral default mode network 16 , unilateral gliomas were found to disrupt long-range inter-hemispheric connectivity 17 , and restricted lesions to induce a global reconfiguration of network complexity 18 .…”

Glioblastoma surgery related emotion recognition deficits are associated with right cerebral hemisphere tract changes

“…We applied 0.2 threshold to the FA skeleton to account for cerebrospinal fluid partial volume effects ( Smith et al , 2006 ) and possibly oedema-related partial volume effects. The FA decreases may represent changes in global connectivity from the disease ( Stoecklein et al , 2020 ) or local WM integrity from injury during tumour resection. Myelin sheets and axonal membranes restrict diffusion perpendicular to their axis, hence isotropic water diffusion (lower FA values) could reflect decreased axonal membrane integrity ( Beaulieu, 2002 ); potentially exacerbated by surgery.…”

Machine Learning Analytics of Resting-State Functional Connectivity Predicts Survival Outcomes of Glioblastoma Multiforme Patients

“…Increasingly, it has become clear that brain networks and their alterations associated with GBM have an impact on survival. Stoecklein et al demonstrated that resting-state functional connectivity (rsFC) measured by MRI is affected by gliomas throughout the whole brain and this information indicated individual glioma disease burden ( 17 ). Daniel et al took these findings further to show that functionally connected voxels can be routinely found within glioblastoma tumors and that intra-tumor connectivity strength is a prognostic marker for overall survival ( 18 ).…”