Objective The brain's functional architecture of interconnected network-related oscillatory patterns in discrete cortical regions has been well established with functional magnetic resonance imaging (fMRI) studies or direct cortical electrophysiology from electrodes placed on the surface of the brain, or electrocorticography (ECoG). These resting state networks exhibit a robust functional architecture that persists through all stages of sleep and under anesthesia. While the stability of these networks provides a fundamental understanding of the organization of the brain, understanding how these regions can be perturbed is also critical in defining the brain's ability to adapt while learning and recovering from injury. Methods Patients undergoing an awake craniotomy for resection of a tumor were studied as a unique model of an evolving injury to help define how the cortical physiology and the associated networks were altered by the presence of an invasive brain tumor. Results This study demonstrates that there is a distinct pattern of alteration of cortical physiology in the setting of a malignant glioma. These changes lead to a physiologic sequestration and progressive synaptic homogeneity suggesting that a de-learning phenomenon occurs within the tumoral tissue compared to its surroundings. Significance These findings provide insight into how the brain accommodates a region of defunctionalized cortex. Additionally, these findings may have important implications for emerging techniques in brain mapping using endogenous cortical physiology.