Safety of Subdural Direct Current Stimulation: A Histological Study in the Ovine Brain

BackgroundDirect current (DC) stimulation can modulate neuronal activity in ways that differ from pulsatile stimulation, but its intracranial use has been limited by concerns about tissue injury at the electrode/tissue interface. Quantitative safety limits for DC delivered through metal electrodes directly to the brain remain poorly defined. ObjectiveTo estimate histological safety boundaries for DC stimulation delivered through metal electrodes in a large-brain gyrencephalic animal model. MethodsCathodal DC stimulation was applied to the exposed cortical surface of ten anesthetized sheep using platinum-iridium disc electrodes typically used in clinical applications (surface area [≤] 4.15 mm2). Currents of 5 to 1000 {micro}A were delivered for 10 to 15 minutes at 36 cortical sites. Stimulation dose was quantified as charge density. Brains were removed shortly after stimulation and examined histologically for tissue damage, including necrosis, inflammation, gliosis, and demyelination. Lesion volumes were quantified and related to charge density. ResultsNo lesions were observed at sites where no current or a low charge density (0.7 mC/mm2) was delivered. With stimulation, lesion probability and volume increased with charge density, although variability was substantial. Lesions occurred in 3 of 18 sites at lower charge densities (1.4 to 10 mC/mm2) and in 5 of 9 sites at higher charge densities (14.4 to 144.4 mC/mm2). Linear regression of lesion volume against charge density yielded an estimated zero-lesion intercept of 2.3 mC/mm2, whereas alternative nonlinear models predicted thresholds up to 8.7 mC/mm2. ConclusionThese findings suggest that it may be possible to apply cathodal DC stimulation directly to the cortical surface through metal electrodes without detectable histological damage when current intensity, duration, and electrode size are appropriately constrained. These findings provide quantitative guidance for the safe application of DC directly to neural tissue in experimental and translational neuromodulation studies.