Gliomas synaptically integrate into neural circuits1,2. Previous research has demonstrated bidirectional interactions between neurons and glioma cells, with neuronal activity driving glioma growth1–4 and gliomas increasing neuronal excitability2,5–8. Here we sought to determine how glioma-induced neuronal changes influence neural circuits underlying cognition and whether these interactions influence patient survival. Using intracranial brain recordings during lexical retrieval language tasks in awake humans together with site-specific tumour tissue biopsies and cell biology experiments, we find that gliomas remodel functional neural circuitry such that task-relevant neural responses activate tumour-infiltrated cortex well beyond the cortical regions that are normally recruited in the healthy brain. Site-directed biopsies from regions within the tumour that exhibit high functional connectivity between the tumour and the rest of the brain are enriched for a glioblastoma subpopulation that exhibits a distinct synaptogenic and neuronotrophic phenotype. Tumour cells from functionally connected regions secrete the synaptogenic factor thrombospondin-1, which contributes to the differential neuron–glioma interactions observed in functionally connected tumour regions compared with tumour regions with less functional connectivity. Pharmacological inhibition of thrombospondin-1 using the FDA-approved drug gabapentin decreases glioblastoma proliferation. The degree of functional connectivity between glioblastoma and the normal brain negatively affects both patient survival and performance in language tasks. These data demonstrate that high-grade gliomas functionally remodel neural circuits in the human brain, which both promotes tumour progression and impairs cognition.
Gliomas synaptically integrate into neural circuits. Prior work has demonstrated bidirectional interactions between neurons and glioma cells, with neuronal activity driving glioma growth and gliomas increasing neuronal excitability. In this study we wanted to know how glioma induced neuronal changes influence neural circuits underlying cognition and whether these interactions influence patient survival. We use intracranial brain recordings during lexical retrieval language tasks in awake humans in addition to site specific tumor tissue biopsies and cell biology experiments. We find that gliomas remodel functional neural circuitry such that task-relevant neural responses activate tumor-infiltrated cortex, beyond cortical excitation normally recruited in the healthy brain. Site-directed biopsies from functionally connected regions within the tumor are enriched for a glioblastoma subpopulation that exhibits a distinct synaptogenic and neuronotrophic phenotype. Tumor cells from functionally connected regions secrete the synaptogenic factor thrombospondin-1, which contributes to the differential neuron-glioma interactions observed in functionally connected tumor regions compared to tumor regions with less functional connectivity. The degree of functional connectivity between glioblastoma and the normal brain negatively impacts both patient survival and language task performance. These data demonstrate that high-grade gliomas functionally remodel neural circuits in the human brain, which both promotes tumor proliferation and impairs cognition.
Objective: One of the greatest challenges of achieving successful surgical outcomes in patients with epilepsy is the ability to properly localize the seizure onset zone (SOZ). Many techniques exist for localizing the SOZ, including intracranial electroencephalography, magnetoencephalography, and stereoelectroencephalography. Recently, resting-state functional magnetic resonance imaging (rs-fMRI) in conjunction with independent component analysis (ICA) has been utilized for presurgical planning of SOZ resection, with varying results. In this meta-analysis, we analyze the current role of rs-fMRI in identifying the SOZ for presurgical planning for patients with drug-resistant epilepsy. Specifically, we seek to demonstrate its current effectiveness compared to other methods of SOZ localization. Methods: A literature review was conducted using the PubMed, MEDLINE, and Embase databases up to May of 2020. A total of 253 articles were screened, and seven studies were chosen for analysis. Each study was analyzed for SOZ localization by ground truth, SOZ localization by rs-fMRI with ICA, principal component analysis, or intrinsic connectivity contrast, and outcomes of surgery. A meta-analysis was performed to analyze how ground truth compares to rs-fMRI in SOZ localization. Results: The odds ratio comparing ground truth to rs-fMRI was 2.63 (95% confidence interval = 0.66-10.56). Average concordance of rs-fMRI SOZ localization compared with ground truth localization across studies was 71.3%. Significance: In the hunt for less invasive presurgical planning for epilepsy surgery, rs-fMRI with ICA provides a promising avenue for future standard practice. Our preliminary results show no significant difference in surgical outcomes between traditional standards of SOZ localization and rs-fMRI with ICA. We believe that rs-fMRI could be a step forward in this search. Further investigation comparing rs-fMRI to traditional methods of SOZ localization should be conducted, with the hope of moving toward relying solely on noninvasive screening methods.
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