Vascular, electrophysiological, and metabolic consequences of cortical spreading depression in a mouse model of simulated neurosurgical conditions

Objectives: Cortical spreading depression (CSD) is a metabolically taxing wave of cellular depolarization that propagates slowly across the brain. Though CSD is known to occur after brain injury in humans, it is unknown if CSD occurs during neurosurgical procedures. This study evaluates CSD in a mouse model of simulated neurosurgical conditions. Methods: Mice were intubated and ventilated, maintained at similar to 37 degrees C, an arterial line placed to monitor mean arterial pressure and maintain pCO(2) similar to 30 mmHg. Mice were given simulated neuroanesthesia (fentanyl, propofol, and isofluorane). Burrholes and craniotomies were made to record the response to cortical bipolar cauterization. Separate sets of experiments (three animals each) examined electrocorticographic (ECoG) activity, optical measures of blood volume and vascular diameters (540 nm absorbance), and autofluorescence attributed to NADH (750 nm, two-photon excitation). Results: Ipsilateral cauterization invariably resulted in a propagating CSD wave identified by slow DC potential shifts (2.8 +/- 0.2 mm/minute, n=6) and suppression of ECoG activity (range 0.5-7.3 minutes, n=10). Each CSD was associated with an initial arteriolar constriction and decreased blood volume, followed by a longer-lasting vasodilation and increased blood volume. Tissue oxygenation, assessed indirectly by NADH imaging, was consistent with demand on oxidative metabolism following each CSD. Repetitive SDs resulted in loss of tissue autofluorescence, suggestive of tissue compromise. Conclusions: CSD is consistently elicited by simulated neurosurgical stimuli under simulated intraoperative conditions in mice. These events caused ECoG depression, transient vasoconstriction, and metabolic demand that propagated from the manipulation site. It is likely that CSD occurs during neurosurgery and may contribute to surgical brain injuries otherwise poorly explained.