Individual Variability of the Human Cerebral Cortex Identified Using Intraoperative Mapping.

BACKGROUND: Intraoperative functional cortical mapping using direct electrical stimulation may show a wider individual variability than suggested by noninvasive imaging data of healthy subjects. METHODS: We assessed intraoperative variability of the frontal eye fields and the speech arrest sites in adult patients who underwent awake craniotomy with direct electrostimulation for treatment of diffuse gliomas located within eloquent regions, and we compared findings with human cortical parcellation of the Human Connectome Project. RESULTS: The frontal eye fields were defined by intraoperative direct electrostimulations (14.3% of patients) projected on the superior subdivision of the premotor cortex covering the areas defined as frontal eye fields (parcel index 10), area 55b (parcel index 12), and premotor eye field (parcel index 11) and in the posterior part of the dorsolateral prefrontal cortex covering the areas defined as inferior 6-8 transitional area (parcel index 97), area 8Av (parcel index 67), and area 8C (parcel index 73). The speech arrest sites were defined by intraoperative direct electrostimulations (100% of patients) projected predominantly posteriorly to the inferior frontal gyrus in the inferior subdivision of the premotor cortex, that is, rostral area 6 (parcel index 78), ventral area 6 (parcel index 54), and area 43 (parcel index 99). CONCLUSIONS: Intraoperative functional cortical mapping using direct electrostimulation highlights that actual individual variability is wider than suggested by analyses of healthy subjects and results in atypical patterns of functional organization and structural and functional changes of the human cerebral cortex under pathologic conditions.

A driver role for GABA metabolism in controlling stem and proliferative cell state through GHB production in glioma.

Cell populations with differing proliferative, stem-like and tumorigenic states co-exist in most tumors and especially malignant gliomas. Whether metabolic variations can drive this heterogeneity by controlling dynamic changes in cell states is unknown. Metabolite profiling of human adult glioblastoma stem-like cells upon loss of their tumorigenicity revealed a switch in the catabolism of the GABA neurotransmitter toward enhanced production and secretion of its by-product GHB (4-hydroxybutyrate). This switch was driven by succinic semialdehyde dehydrogenase (SSADH) downregulation. Enhancing GHB levels via SSADH downregulation or GHB supplementation triggered cell conversion into a less aggressive phenotypic state. GHB affected adult glioblastoma cells with varying molecular profiles, along with cells from pediatric pontine gliomas. In all cell types, GHB acted by inhibiting α-ketoglutarate-dependent Ten-eleven Translocations (TET) activity, resulting in decreased levels of the 5-hydroxymethylcytosine epigenetic mark. In patients, low SSADH expression was correlated with high GHB/α-ketoglutarate ratios, and distinguished weakly proliferative/differentiated glioblastoma territories from proliferative/non-differentiated territories. Our findings support an active participation of metabolic variations in the genesis of tumor heterogeneity.