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NIH grant 1R21NS150992-01: Mapping heterogeneous local excitation profiles to link focal epileptogenesis and tumor growth in IDH-mutant glioma
Institute: {'code': 'NS', 'abbreviation': 'NINDS', 'name': 'National Institute of Neurological Disorders and Stroke', 'admin_org_id': '12500053', 'admin_funding_url': ''}. PI: Patrick Jacob Karas. Award: $242250.
Start: 2026-09-11T00:00:00.
PROJECT SUMMARY
Seizures are the most common and often earliest symptom of isocitrate dehydrogenase–mutant
gliomas (IDHmG), affecting over 90% of patients. Growing evidence shows that glioma cells directly interact
with neurons, increasing network excitability and forming a feedback loop that drives both seizures and tumor
growth. Because seizures also impair quality of life, understanding their mechanisms in IDHmG could improve
neurological outcomes and potentially slow tumor progression. Surgical removal often achieves seizure
freedom, but complete resection is limited by infiltration into eloquent cortex. Residual tumor correlates with
persistent seizures, which appear to arise from discrete intra- or peritumoral zones. A central question is
whether these hyperexcitable areas also represent the most proliferative tumor regions. Defining this
relationship could improve surgical targeting, seizure control, and prognosis. Epileptogenesis in IDHmG likely
stems from localized abnormalities in excitation–inhibition balance across tumor and peritumoral networks. We
propose that these hyperexcitable areas are dual-risk zones for seizures and malignant progression. Using a
multiscale approach, we will integrate intraoperative electrophysiology, ex vivo recordings, and spatial
proteomics to link neuronal hyperexcitability with tumor biology.
During IDHmG resection, depth electrodes will record local field potentials from tumor and surrounding
cortex to identify spontaneous spikes, sharp waves, after-discharges, and seizure events. Offline analyses
including high-frequency oscillation detection, spectral dynamics, functional connectivity and electromagnetic
source localization will quantify excitability gradients and relate them to histopathology and postoperative
seizure outcomes. To identify the underlying cellular mechanisms, acute tumor slices will undergo whole-cell
patch-clamp and field recordings to measure intrinsic neuronal and synaptic properties. We will test whether
hyperexcitable regions show increased excitatory drive or reduced inhibitory tone and assess receptor-specific
contributions of AMPA and GABA_A pathways. Finally, to define molecular correlation, synaptosomes from
electrophysiologically defined regions will be analyzed by microtransplantation electrophysiology and mass
spectrometry to detect proteins linked to excitatory signaling. Parallel assays will assess proliferation and
malignancy markers to connect excitability with tumor aggressiveness.
This study will bridge neurophysiology and tumor biology to explain how neuronal hyperexcitability
drives IDHmG behavior. By integrating electrophysiological, cellular, and molecular data, it will establish a
framework for identifying epileptogenic and biologically active tumor regions during surgery. Insights from this
work could refine resection strategies and guide therapies that reduce seizures while limiting tumor
progression.document fetched 2026-09-20 02:42