CNSC-95. GLIOMA-INFILTRATION INDUCES DRUG-RESPONSIVE MULTISCALE REMODELING OF HUMAN CORTICAL CIRCUITRY

Abstract Diffuse gliomas infiltrate the cerebral cortex and profoundly alter brain function, yet the multiscale consequences of this invasion on human neural circuits remain poorly understood. Here, we integrate magnetoencephalography (MEG), electrocorticography, spatial transcriptomics, single-nucleus RNA sequencing, and high density single-unit Neuropixels recordings from WHO grade 2-4 glioma patients to interrogate the structural and functional integrity of infiltrated neocortex. We identify a reproducible gain of laminar dependent synaptic gene expression in glioma-infiltrated regions (n = 10 samples; 29,011 spots), strongly correlated with local tumor proliferation (n = 6 patients) despite greater tumor burden in deeper cortical layers (n = 19 patients). Single-nucleus profiling and deconvolution revealed subtype-specific vulnerability of neuronal subclasses accompanied by transcriptomic reprogramming. Single-unit analysis across cortical depth (n = 11 patients) highlighted a profound reduction in overall unit yield and spiking activity (Controls = 169.5 units vs Glioma-infiltrated cortex = 35 units, p-value < 0.05, Mann-Whitney Test) within glioma-infiltrated cortex, with selective loss of excitatory and inhibitory neurons. This cell-type-specific vulnerability varied by glioma subtype and cortical layer, with astrocytoma showing the greatest excitatory loss in deep layers. Power spectral analysis across depth revealed altered laminar oscillatory structure in infiltrated regions—characterized by increased delta (1–4 Hz) and depth-dependent decreases in beta (12–20 Hz) power—mirroring noninvasive MEG findings (n = 144 patients) and partially restored under propofol anesthesia. Cross-modal integration uncovered a core axis linking tumor infiltration, neuron loss, and circuit dysfunction across cortical layers. These findings define laminar signatures of glioma-induced cortical dysfunction, establish a foundational framework for mapping glioma-driven cortical collapse and identify therapeutic windows for circuit-level rescue in brain cancer.