## 4 Discussion  
We demonstrated that resting-state fMRI and graph-theoretical measures could capture differences in network dynamics associated with tumor grade and location. Graph-theoretical measures demonstrated increased global efficiency for the left hemispheric network in LGG and decreased cost and degree for the right hemispheric network in HGG (Figure 3). We can highlight two main points of clinical significance for our results: (1) the evidence of connectivity disruption in distant areas from HGG supports the notion of the 'whole-brain' nature of this disease, differently from LGG, which displayed predominantly local effects within the same hemisphere. (2) By analyzing specific graph-theoretical metrics which describe the efficiency of information transfer in a network, we found that low-grade tumors may show more favorable network changes than high-grade tumors, in agreement with participating patients' clinical deficits. These findings support the idea that LGG leads to functional reorganization of the eloquent cortex in the same hemisphere resulting in increased efficiency of the network. On the contrary, HGG displayed decreased network connectedness, as well as more profound clinical deficits. The increased global efficiency of the left hemispheric network in LGG patients points to higher inter-connectedness of the network compared to HC. Similarly, [PERSON] et al. described increased connectivity between hubs and non-hubs in glioma patients compared to healthy subjects. Such network modifications may be related to intra-hemispheric reorganization, which has been described in LGG, especially in regard to the language network [6; 20]. Functional reorganization in LGG has been attributed to their characteristic slow pace of growth, which is believed to facilitate the development of plastic changes. In addition to prior evidence, our results may support the idea of a beneficial intra-hemispheric reorganization in LGG related to increased global efficiency of the left hemispheric network, in agreement with our original hypothesis. Indeed, LGG demonstrated significantly better clinical performance than HGG for language function, which is generally left-lateralized. When comparing the left vs. right hemisphere in LGG, the left side demonstrated increased global efficiency, decreased local efficiency and decreased clustering coefficient. These modifications point to a higher inter-connectedness of the entire left-hemispheric network, with decreased locality (sub-graphs are less inter-connected within their neighborhood and more connected to the entire network). Based on these findings, a type of functional reorganization characterized by the recruitment of additional brain regions within the left hemisphere may be hypothesized, leading to a shift from locality to global efficiency. In HGG patients, a decrease in all graph-theory metrics compared to HC was seen in the left hemisphere (supplementary Table S6), although without reaching statistical significance. Peritumoral depression of the blood-oxygen level dependent (BOLD) signal is expected in some high-grade tumors due to neurovascular uncoupling [21; 22], with possible local effects on connectivity [23]. The fact that left-hemispheric functional changes in HGG did not reach statistical significance in our cohort may be due to relatively small tumor size and/or it may be related to the limitations of our study. In fact, lobar network analysis identified significant left- and right-sided changes in both HGG and LGG. This difference is likely due to the fact that the hemispheric network is averaged across HGG, while the lobar analysis investigates subgroups of HGG according to their lobar location, unraveling smaller effects on connectivity that may be otherwise undetected. Hemispheric network analysis in HGG showed significant right-sided changes (decreased cost and degree). Growing evidence supports the idea of gliomas having a global effect on brain functioning, with alterations in brain regions remote from the tumor [12].