{"id":{"repo_id":"cambridge","oai_identifier":"oai:www.repository.cam.ac.uk:1810/364762"},"canonical_url":"https://search.dev.ndltd.org/etd/cambridge/oai:www.repository.cam.ac.uk:1810/364762","repository":{"repo_id":"cambridge","name":"Cambridge University","base_url":"https://api.repository.cam.ac.uk/server/oai/request"},"display":{"title":"Elucidating the Principles of Brain Network Organisation through Neurosurgery","abstract":"Recently, leaders in human brain mapping and the clinical neurosciences outlined the need for prospective trials in neurosurgery to establish the clinical relevance of connectomics. This doctoral dissertation addresses this challenge by using diffuse gliomas as a model to study the principles of brain network organisation through neurosurgery. Specifically, I combined insight from a normative cohort of healthy individuals across the lifespan with a highly rare neurosurgical cohort of diffuse glioma patients who underwent longitudinal connectomic and cognitive testing throughout their clinical care. By understanding how gliomas infiltrate eloquent cortex with little to no cognitive deficits, we may be able to better understand the brain and cancer and ultimately devise new treatment approaches. Overall, the twin scientific and clinical aims were to i) understand how gliomas embed themselves within circuits governing higher-order cognition and ii) determine the utility of connectomics in mapping higher-order cognitive functions for presurgical planning and postsurgical rehabilitation. In the first set of investigations, I deployed structural connectomics to demonstrate that the structural integrity of the Multiple Demand (MD) system for domain-general cognition uniquely predicts interindividual differences in executive functioning across the lifespan. I then demonstrated that diffuse gliomas primarily co-localise to the MD system’s core frontoparietal network, with connectomic, transcriptomic, and neurochemical analyses revealing that connector hubs, oligodendrocyte precursor cells (OPCs), and proto-oncogenes are uniquely enriched in the MD system making it vulnerable to oncogenesis. When investigating the cognitive impact of gliomas infiltrating the MD system, the data reveals long-term cognitive improvements, indicating the brain underwent structural changes to accommodate the tumour and consequently minimize its impact. Presurgical structural analyses of glioma patients’ brains revealed decreases in cortical thickness in the MD system and homotopic areas compared to age- and sex-matched controls. Remarking, normative modelling revealed that the presence of gliomas induced cortical thinning and accelerated ‘brain ageing’, which was partially normalised following surgery and more consistent with healthy adults. In the second set of investigations, I complemented the structural investigation with functional connectomics to demonstrate that gliomas strategically embed themselves within hierarchical gradients and that long-term cognitive deficits result from increased cortical gradient dispersion. Given that meningiomas exert their deleterious effects by compressing brain tissue whereas gliomas infiltrate the tissue, contrasting both patient groups with healthy controls, gliomas decreased global gradient dispersion whereas meningiomas did not. More regionally, to assess mesoscale cortical dynamics, resecting more presurgical connector hubs leads to long-term cognitive deficits whereas resecting provincial hubs did not cause long-term deficits. In addition, changes in perioperative modularity differentiated patients with long-term cognitive deficits from those with long-term improvements. Finally, in the last section of this dissertation, I deployed interventional connectomics to demonstrate how non-invasive brain stimulation is safe and can be utilised in the perioperative setting to promote functional recovery and potentially accelerate long-term cognitive outcomes. Specifically, transcranial magnetic stimulation can be safely applied without causing seizures to improve deficits in motor or language function. In summary, this dissertation presents new evidence on how gliomas embed themselves within the connectome and the clinical utility of connectomics for neurosurgery. Based on connectomic data, the stage is set for future studies to carry this work forward with prospective randomized clinical trials (RCTs) on modulating the presurgical connectome and/or accelerating postsurgical cognitive rehabilitation. Finally, I conclude with providing future directions on how systems neuroscience and functional neurosurgery can be strategically combined to advance the emerging field of cancer neuroscience.","abstract_html":"Recently, leaders in human brain mapping and the clinical neurosciences outlined the need for prospective trials in neurosurgery to establish the clinical relevance of connectomics. This doctoral dissertation addresses this challenge by using diffuse gliomas as a model to study the principles of brain network organisation through neurosurgery. Specifically, I combined insight from a normative cohort of healthy individuals across the lifespan with a highly rare neurosurgical cohort of diffuse glioma patients who underwent longitudinal connectomic and cognitive testing throughout their clinical care. By understanding how gliomas infiltrate eloquent cortex with little to no cognitive deficits, we may be able to better understand the brain and cancer and ultimately devise new treatment approaches. Overall, the twin scientific and clinical aims were to i) understand how gliomas embed themselves within circuits governing higher-order cognition and ii) determine the utility of connectomics in mapping higher-order cognitive functions for presurgical planning and postsurgical rehabilitation. In the first set of investigations, I deployed structural connectomics to demonstrate that the structural integrity of the Multiple Demand (MD) system for domain-general cognition uniquely predicts interindividual differences in executive functioning across the lifespan. I then demonstrated that diffuse gliomas primarily co-localise to the MD system’s core frontoparietal network, with connectomic, transcriptomic, and neurochemical analyses revealing that connector hubs, oligodendrocyte precursor cells (OPCs), and proto-oncogenes are uniquely enriched in the MD system making it vulnerable to oncogenesis. When investigating the cognitive impact of gliomas infiltrating the MD system, the data reveals long-term cognitive improvements, indicating the brain underwent structural changes to accommodate the tumour and consequently minimize its impact. Presurgical structural analyses of glioma patients’ brains revealed decreases in cortical thickness in the MD system and homotopic areas compared to age- and sex-matched controls. Remarking, normative modelling revealed that the presence of gliomas induced cortical thinning and accelerated ‘brain ageing’, which was partially normalised following surgery and more consistent with healthy adults. In the second set of investigations, I complemented the structural investigation with functional connectomics to demonstrate that gliomas strategically embed themselves within hierarchical gradients and that long-term cognitive deficits result from increased cortical gradient dispersion. Given that meningiomas exert their deleterious effects by compressing brain tissue whereas gliomas infiltrate the tissue, contrasting both patient groups with healthy controls, gliomas decreased global gradient dispersion whereas meningiomas did not. More regionally, to assess mesoscale cortical dynamics, resecting more presurgical connector hubs leads to long-term cognitive deficits whereas resecting provincial hubs did not cause long-term deficits. In addition, changes in perioperative modularity differentiated patients with long-term cognitive deficits from those with long-term improvements. Finally, in the last section of this dissertation, I deployed interventional connectomics to demonstrate how non-invasive brain stimulation is safe and can be utilised in the perioperative setting to promote functional recovery and potentially accelerate long-term cognitive outcomes. Specifically, transcranial magnetic stimulation can be safely applied without causing seizures to improve deficits in motor or language function. In summary, this dissertation presents new evidence on how gliomas embed themselves within the connectome and the clinical utility of connectomics for neurosurgery. Based on connectomic data, the stage is set for future studies to carry this work forward with prospective randomized clinical trials (RCTs) on modulating the presurgical connectome and/or accelerating postsurgical cognitive rehabilitation. Finally, I conclude with providing future directions on how systems neuroscience and functional neurosurgery can be strategically combined to advance the emerging field of cancer neuroscience.","abstract_has_math":false,"creators":["Poologaindran, Anujan"],"institution":"University of Cambridge","degree_name":"Doctor of Philosophy (PhD)","degree_level":"Doctoral","degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":["Suckling, John"],"committee_chairs":[],"committee_members":[],"year":2022,"date_issued":"2022-08-01","date_published":"2022-08-01","updated_at":"2026-07-22T22:24:20Z","subjects":["brain mapping","brain stimulation","cognitive testing","connectomics","neurosurgery","transcriptomics"],"languages":["eng"],"rights":[],"rights_urls":["https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/1a3ac480-b04a-45a7-98f3-a366ebf5fe7a/download","https://www.rioxx.net/licenses/all-rights-reserved/"],"identifier_entries":[]},"links":{"outbound_url":"https://doi.org/10.17863/CAM.106302","outbound_label":"DOI","outbound_source":"dc:identifier.doi"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Suckling, John"]},{"key":"dc:contributor.sponsor","label":"Sponsor","values":["The Alan Turing Institute (the Turing). 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Presurgical structural analyses of glioma patients’ brains revealed decreases in cortical thickness in the MD system and homotopic areas compared to age- and sex-matched controls. Remarking, normative modelling revealed that the presence of gliomas induced cortical thinning and accelerated ‘brain ageing’, which was partially normalised following surgery and more consistent with healthy adults. In the second set of investigations, I complemented the structural investigation with functional connectomics to demonstrate that gliomas strategically embed themselves within hierarchical gradients and that long-term cognitive deficits result from increased cortical gradient dispersion. Given that meningiomas exert their deleterious effects by compressing brain tissue whereas gliomas infiltrate the tissue, contrasting both patient groups with healthy controls, gliomas decreased global gradient dispersion whereas meningiomas did not. More regionally, to assess mesoscale cortical dynamics, resecting more presurgical connector hubs leads to long-term cognitive deficits whereas resecting provincial hubs did not cause long-term deficits. In addition, changes in perioperative modularity differentiated patients with long-term cognitive deficits from those with long-term improvements. Finally, in the last section of this dissertation, I deployed interventional connectomics to demonstrate how non-invasive brain stimulation is safe and can be utilised in the perioperative setting to promote functional recovery and potentially accelerate long-term cognitive outcomes. Specifically, transcranial magnetic stimulation can be safely applied without causing seizures to improve deficits in motor or language function. In summary, this dissertation presents new evidence on how gliomas embed themselves within the connectome and the clinical utility of connectomics for neurosurgery. 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When investigating the cognitive impact of gliomas infiltrating the MD system, the data reveals long-term cognitive improvements, indicating the brain underwent structural changes to accommodate the tumour and consequently minimize its impact. Presurgical structural analyses of glioma patients’ brains revealed decreases in cortical thickness in the MD system and homotopic areas compared to age- and sex-matched controls. Remarking, normative modelling revealed that the presence of gliomas induced cortical thinning and accelerated ‘brain ageing’, which was partially normalised following surgery and more consistent with healthy adults. In the second set of investigations, I complemented the structural investigation with functional connectomics to demonstrate that gliomas strategically embed themselves within hierarchical gradients and that long-term cognitive deficits result from increased cortical gradient dispersion. Given that meningiomas exert their deleterious effects by compressing brain tissue whereas gliomas infiltrate the tissue, contrasting both patient groups with healthy controls, gliomas decreased global gradient dispersion whereas meningiomas did not. More regionally, to assess mesoscale cortical dynamics, resecting more presurgical connector hubs leads to long-term cognitive deficits whereas resecting provincial hubs did not cause long-term deficits. In addition, changes in perioperative modularity differentiated patients with long-term cognitive deficits from those with long-term improvements. Finally, in the last section of this dissertation, I deployed interventional connectomics to demonstrate how non-invasive brain stimulation is safe and can be utilised in the perioperative setting to promote functional recovery and potentially accelerate long-term cognitive outcomes. Specifically, transcranial magnetic stimulation can be safely applied without causing seizures to improve deficits in motor or language function. In summary, this dissertation presents new evidence on how gliomas embed themselves within the connectome and the clinical utility of connectomics for neurosurgery. Based on connectomic data, the stage is set for future studies to carry this work forward with prospective randomized clinical trials (RCTs) on modulating the presurgical connectome and/or accelerating postsurgical cognitive rehabilitation. 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