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.

Recent developments in the biology of malignant gliomas have demonstrated that glioma cells interact with neurons through both paracrine signaling and electrochemical synapses. Glioma–neuron interactions consequently modulate the excitability of local neuronal circuits, and it is unclear the extent to which glioma-infiltrated cortex can meaningfully participate in neural computations. For example, gliomas may result in a local disorganization of activity that impedes the transient synchronization of neural oscillations. Alternatively, glioma-infiltrated cortex may retain the ability to engage in synchronized activity in a manner similar to normal-appearing cortex but exhibit other altered spatiotemporal patterns of activity with subsequent impact on cognitive processing. Here, we use subdural electrocorticography to sample both normal-appearing and glioma-infiltrated cortex during speech. We find that glioma-infiltrated cortex engages in synchronous activity during task performance in a manner similar to normal-appearing cortex but recruits a diffuse spatial network. On a temporal scale, we show that signals from glioma-infiltrated cortex have decreased entropy, which may affect its ability to encode information during nuanced tasks such as production of monosyllabic versus polysyllabic words. Furthermore, we show that temporal decoding strategies for distinguishing monosyllabic from polysyllabic words were feasible for signals arising from normal-appearing cortex but not from glioma-infiltrated cortex. These findings inform our understanding of cognitive processing in chronic disease states and have implications for neuromodulation and prosthetics in patients with malignant gliomas.

OBJECTIVEMaximal safe tumor resection in language areas of the brain relies on a patient’s ability to perform intraoperative language tasks. Assessing the performance of these tasks during awake craniotomies allows the neurosurgeon to identify and preserve brain regions that are critical for language processing. However, receiving sedation and analgesia just prior to experiencing an awake craniotomy may reduce a patient’s wakefulness, leading to transient language and/or cognitive impairments that do not completely subside before language testing begins. At present, the degree to which wakefulness influences intraoperative language task performance is unclear. Therefore, the authors sought to determine whether any of 5 brief measures of wakefulness predicts such performance during awake craniotomies for glioma resection.METHODSThe authors recruited 21 patients with dominant hemisphere low- and high-grade gliomas. Each patient performed baseline wakefulness measures in addition to picture-naming and text-reading language tasks 24 hours before undergoing an awake craniotomy. The patients performed these same tasks again in the operating room following the cessation of anesthesia medications. The authors then conducted statistical analyses to investigate potential relationships between wakefulness measures and language task performance.RESULTSRelative to baseline, performance on 3 of the 4 objective wakefulness measures (rapid counting, button pressing, and vigilance) declined in the operating room. Moreover, these declines appeared in the complete absence of self-reported changes in arousal. Performance on language tasks similarly declined in the intraoperative setting, with patients experiencing greater declines in picture naming than in text reading. Finally, performance declines on rapid counting and vigilance wakefulness tasks predicted performance declines on the picture-naming task.CONCLUSIONSCurrent subjective methods for assessing wakefulness during awake craniotomies may be insufficient. The administration of objective measures of wakefulness just prior to language task administration may help to ensure that patients are ready for testing. It may also allow neurosurgeons to identify patients who are at risk for poor intraoperative performance.

OBJECTIVE The supplementary motor area (SMA) is an eloquent region that is frequently a site for glioma, or the region is included in the resection trajectory to deeper lesions. Although the clinical relevance of SMA syndrome has been well described, it is still difficult to predict who will become symptomatic. The object of this study was to define which patients with SMA gliomas would go on to develop a postoperative SMA syndrome. METHODS The University of California, San Francisco, tumor registry was searched for patients who, between 2010 and 2019, had undergone resection for newly diagnosed supratentorial diffuse glioma (WHO grades II–IV) performed by the senior author and who had at least 3 months of follow-up. Pre- and postoperative MRI studies were reviewed to confirm the tumor was located in the SMA region, and the extent of SMA resection was determined by volumetric assessment. Patient, tumor, and outcome data were collected retrospectively from documents available in the electronic medical record. Tumors were registered to a standard brain atlas to create a frequency heatmap of tumor volumes and resection cavities. RESULTS During the study period, 56 patients (64.3% male, 35.7% female) underwent resection of a newly diagnosed glioma in the SMA region. Postoperatively, 60.7% developed an SMA syndrome. Although the volume of tumor within the SMA region did not correlate with the development of SMA syndrome, patients with the syndrome had larger resection cavities in the SMA region (25.4% vs 14.2% SMA resection, p = 0.039). The size of the resection cavity in the SMA region did not correlate with the severity of the SMA syndrome. Patients who developed the syndrome had cavities that were located more posteriorly in the SMA region and in the cingulate gyrus. When the frontal aslant tract (FAT) was preserved, 50% of patients developed the SMA syndrome postoperatively, whereas 100% of the patients with disruption of the FAT during surgery developed the SMA syndrome (p = 0.06). Patients with SMA syndrome had longer lengths of stay (5.6 vs 4.1 days, p = 0.027) and were more likely to be discharged to a rehabilitation facility (41.9% vs 0%, p < 0.001). There was no difference in overall survival for newly diagnosed glioblastoma patients with SMA syndrome compared to those without SMA syndrome (1.6 vs 3.0 years, p = 0.33). CONCLUSIONS For patients with SMA glioma, more extensive resections and resections involving the posterior SMA region and posterior cingulate gyrus increased the likelihood of a postoperative SMA syndrome. Although SMA syndrome occurred in all cases in which the FAT was resected, FAT preservation does not reliably avoid SMA syndrome postoperatively.

BACKGROUND:Increases in the extent of resection of both contrast-enhanced (CE) and non–contrast-enhanced (NCE) tissue are associated with substantial survival benefits in patients with isocitrate dehydrogenase wild-type glioblastoma. The fact, however, remains that these lesions exist within the framework of complex neural circuitry subserving cognition, movement, and behavior, all of which affect the ultimate survival outcome. The prognostic significance of the interplay between CE and NCE cytoreduction and neurological morbidity is poorly understood.OBJECTIVE:To identify a clinically homogenous population of 228 patients with newly diagnosed isocitrate dehydrogenase wild-type glioblastoma, all of whom underwent maximal safe resection of CE and NCE tissue and adjuvant chemoradiation. We then set out to delineate the competing interactions between resection of CE and NCE tissue and postoperative neurological impairment with respect to overall survival.METHODS:Nonparametric multivariate models of survival were generated via recursive partitioning to provide a clinically intuitive framework for the prognostication and surgical management of such patients.RESULTS:We demonstrated that the presence of a new postoperative neurological impairment was the key factor in predicting survival outcomes across the entire cohort. Patients older than 60 yr who suffered from at least one new impairment had the worst survival outcome regardless of extent of resection (median of 11.6 mo), whereas those who did not develop a new impairment had the best outcome (median of 28.4 mo) so long as all CE tissue was resected.CONCLUSION:Our data provide novel evidence for management strategies that prioritize safe and complete resection of CE tissue.

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Lexical retrieval requires selecting and retrieving the most appropriate word from the lexicon to express a desired concept. Few studies have probed lexical retrieval with tasks other than picture naming, and when non-picture naming lexical retrieval tasks have been applied, both convergent and divergent results emerged. The presence of a single construct for auditory and visual processes of lexical retrieval would influence cognitive rehabilitation strategies for patients with aphasia. In this study, we perform support vector regression lesion-symptom mapping using a brain tumor model to test the hypothesis that brain regions specifically involved in lexical retrieval from visual and auditory stimuli represent overlapping neural systems. We find that principal components analysis of language tasks revealed multicollinearity between picture naming, auditory naming, and a validated measure of word finding, implying the existence of redundant cognitive constructs. Nonparametric, multivariate lesion-symptom mapping across participants was used to model accuracies on each of the four language tasks. Lesions within overlapping clusters of 8,333 voxels and 21,512 voxels in the left lateral prefrontal cortex (PFC) were predictive of impaired picture naming and auditory naming, respectively. These data indicate a convergence of heteromodal lexical retrieval within the PFC.