Cellular, Connectomic, and Cognitive Impact of Glioma and its Surgical Resection

Awake surgery with intraoperative direct electrical stimulation (DES) is the gold-standard to maximize the extent of resection in diffuse cerebral gliomas (Duffau et al. 2023). While this approach is effective in testing for simple motor and language functions, it is inadequate for mapping higher-order cognitive functions such as attention, working memory, and cognitive control. Given that systems neuroscience is moving away from a localizationist to a connectomic perspective of human brain function, ideally, we could better understand how gliomas integrate within the connectome and how performing surgery on the brain’s mesoscale hub architecture affects long-term cognitive outcomes. To address problem, we combined cellular, connectomic, and cognitive data from healthy individuals (n=629) across the lifespan, cross-sectional glioma imaging (n=98), the Allan Human Brain Atlas (n=6), and a rare cohort of diffuse glioma patients (n=17) followed longitudinally as they underwent neurosurgery. First, we validate that meta-analytic cognitive activation maps co-localize with the Multiple Demand (MD) system and show that diffuse gliomas preferentially localize to the ‘core’ of this brain network. Second, cellular decoding of the MD core network reveals that it is uniquely enriched with oligodendrocyte precursor cells, glioma proto-oncogenes, and 5HT2-serotonergic neurotransmission. Third, the MD system is preferentially enriched for connector hubs to scaffolding the brain’s mesoscale hub architecture and that diffuse gliomas induce reorganization in this architecture thereby minimizing cognitive deficits. Lastly, surgical resection of connector, rather than provincial, hubs leads to long-term cognitive deficits while maintenance or dissolution of interhemispheric modularity predicted long-term cognitive outcomes. With the recent demonstration of the high concordance between DES and functional brain mapping (Saurrubo et al. 2024), this study provides new insight into how gliomas integrate within the connectome and that mapping the mesoscale hub architecture in each patient may improve presurgical mapping and postsurgical rehabilitation. Given the small but deeply sampled neurosurgical cohort, additional studies are now warranted to assess the value of mapping mesoscale connectivity for presurgical mapping and ‘interventional neurorehabilitation’ (Poologaindran et al. 2022).