Spreading depression (SD), a pathological cortical negative DC potential, is caused by an elevation of potassium ions in the extracellular space. This leads to a transient relocation of ions within neurons and a slow spread through brain tissue. Our previous research established a correlation between scalp SD and seizures in patients with intractable epilepsy using our novel electroencephalography (EEG). In this study, we enhanced our EEG system by incorporating a Near-infrared spectroscopy (NIRS) module for multi-modal EEG-NIRS measurements. The aim is to provide an investigation into the defining characteristics and methods for detecting SD.Clinical Relevance—: The detection of SD serves as a novel biomarker for epilepsy, capable of forewarning seizures within a time range from 10 secs to 30 min. This detection plays a crucial role in predicting and preventing seizures and providing diagnostic information for drug-resistant epilepsy patients.