Researchers from the University of California at San Francisco have conducted a study on how glioma-induced neuronal alterations impact the cognitive functioning of the brain and if these changes affect a patient’s survival. Gliomas are a type of tumour-forming cell that can alter the functional neural circuits in the brain, thereby activating tumour-infiltrated white matter beyond the usual cortical regions engaged in a healthy brain during language tasks involving lexical retrieval. The study, which was published in Nature under the title “Glioblastoma Remodelling of Human Neural Circuits Decreases Survival”, demonstrates how glioblastoma infiltration physically remodels functional neural circuitry.
Lexical retrieval involves processing the concept in the brain while speaking, from concept to the utterance. Neural processing of speech can vary by word complexity and frequency of use, with vocalising less frequently used words requiring more complicated coordination than commonly used (high-frequency) words.
Several factors can impact the lexical retrieval process, including uncommonly used words with weaker neural reinforcement and interference from neurodegeneration, where synaptic connections along the retrieval route are destroyed or remodelled in such a way as to make the connections inoperable. Patients with glioma often experience lexical retrieval issues, but whether the tumours remodel or destroy the neuronal circuits in the process pathway was unknown.
Normal brain tissue produced above-chance decoding between low- and high-frequency word trials in experimental conditions. By contrast, glioblastoma-infiltrated brain tissue did not decode word trials above chance. This showed to the researchers that glioblastoma infiltration maintains task-specific neuronal responses, the task of accessing a word, yet the tumour-affected brain regions lose the ability to decode complex or low-frequency words.
Using intracranial brain recordings during lexical retrieval language tasks, tumour tissue biopsies, and cell biology experiments, the team found that gliomas physically remodel functional neural circuitry. Task-relevant neural responses activated tumour-inflated cortex areas well beyond the cortical regions usually recruited in the healthy brain. Biopsies from these tumour regions that exhibited high functional connectivity with the rest of the brain were enriched with a specific glioblastoma subpopulation that shows a distinct synaptogenic and neurotrophic phenotype – synaptogenic factor thrombospondin-1 (TSP-1).
TSP-1 is a synaptogenic factor secreted in the healthy brain by astrocytes and is associated with the assembly of neural circuits, including synapse-associated genes and axon pathfinding genes. TSP-1 has long been associated with gliomas and is known to play a role in the mechanisms that control changes to neuronal morphology and brain plasticity.
The study also found feedback between high-grade gliomas and neural networks, with neuronal activity promoting glioma growth while gliomas increase neuronal excitability. TSP-1-expressing malignant cells interacted with neuronal signals, exhibiting a synaptogenic, proliferative, invasive, and integrative profile. The TSP-1 tumours were effectively hijacking cognitive function, the act of lexicon retrieval, to fuel their growth and create more connections beyond the usual retrieval process to aid their spread.
Mice with functional connectivity between the tumour and the rest of the brain had a shorter overall survival than those without TSP-1-expressing malignant cells. The degree of functional connectivity between glioblastoma and the normal brain was negatively correlated with both mouse survival and human performance in language tasks. Inhibition of TSP-1 using the FDA-approved drug gabapentin decreased glioblastoma cell proliferation and network synchrony, suggesting a potential therapeutic intervention strategy in the future.
In summary, the study underscores the need for further research into the role of gliomas in remodelling functional neural circuitry to better understand their mechanisms of action and identify novel therapeutic targets.
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In conclusion, this study sheds light on the bidirectional feedback relationship between high-grade gliomas and neural networks. The findings show that gliomas can alter functional neural circuits in the brain, hijacking cognitive functions like lexical retrieval to fuel their growth and create more connections beyond the usual neural pathways to further their spread. The study also highlights the potential of inhibiting synaptogenic factor thrombospondin-1 (TSP-1) using FDA-approved drugs like gabapentin as a possible future therapeutic intervention strategy. These findings could have significant implications in developing new and more effective treatments for patients with glioma, ultimately improving their overall survival.
