The possible use of impedance measurement with scalp electrodes to detect intracranial events non-invasively was investigated by measuring the localised impedance changes during cortical spreading depression (CSD) in anaesthetised rats. Impedance was measured over ipsilateral fronto-parietal cortex by a four electrode method operating at 50 kHz with electrodes spaced 0.5 mm apart. Cortical impedance increased by 39% of the resting level during CSD. With scalp electrodes placed on abraded skin, an unexpected impedance decrease of 0.8% occurred, which correlated spatially and temporally with CSD. CSD was accompanied by a small rise in temperature; when scalp temperature was held constant by warming the scalp, no impedance change greater than baseline variability (+/- 0.1% of the resting impedance level) was observed. The non-invasive detection of CSD in migraine in humans may be possible by measuring the characteristic temperature-related impedance changes with Electrical Impedance Tomography and scalp electrodes.