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 brains 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 brains 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). ### Competing Interest Statement MES is the co-founder of Omniscient Neurotechnology ### Funding Statement This research was supported by the Alan Turing Institute and NSERC grants. It was also supported by a Guarantors of Brain, Cancer Research UK Cambridge Centre, The Brain Tumour Charity and the EMERGIA Junta de Andalucia program. Y.E. is funded by a Royal Society Dorothy Hodgkin Research Fellowship (DHF130100). MA was funded by a Cambridge Trust Yousef Jameel Scholarship. This research was also supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). SJP (NIHR Career Development Fellowship, CDF-2018-11-ST2-003) is funded by the National Institute for Health Research (NIHR) for this research project. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was approved by the Cambridge Central Research Ethics Committee (Reference number 16/EE/0151) and all patients provided written informed consent I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors