Electrochemical safety limits for clinical stimulation investigated using depth and strip electrodes in the pig brain

Objective. Diagnostic and therapeutic electrical stimulation are increasingly utilized with the rise of neuromodulation devices. However, systematic investigations that depict the practical clinical stimulation paradigms (bipolar, two-electrode configuration) to determine the safety limits are currently lacking. Further, safe charge densities that were classically determined from conical sharp electrodes are generalized for cylindrical (depth) and flat (surface grid) electrodes completely ignoring geometric factors that govern current spreading and trajectories in tissue.Approach. This work reports the first investigations comparing stimulation limits for clinically used electrodes in two mediums: in benchtop experiments in saline andin vivoin a single acute experiment in the pig brain. We experimentally determine the geometric factors, the water electrolysis windows, and the current safety limits from voltage transients, for the sEEG, depth and surface strip electrodes in both mediums. Using four-electrode and three-electrode configuration measurements and comprehensive circuit models that accurately depict our measurements, we delineate the various elements of the stimulation medium, including the tissue-electrode interface impedance spectra, the medium impedance and the bias-dependent change in the interface impedance as a function of stimulation parameters.Main results. The results of our systematics studies suggest that safe currents in clinical bipolar stimulation determinedin vivocan be as much as 24 times smaller than those determined from benchtop experiments (for depth electrodes at a 1 ms pulse duration). Our detailed circuit modeling attributes this drastic difference in safe limits to the greatly dissimilar electrode/tissue and electrode/saline impedances.Significance. We established the electrochemical safety limits for commonly used clinical electrodesin vivoand revealed by detailied electrochemical modeling how they differ from benchtop evaluation. We argue that electrochemical limits and currents are unique for each electrode, should be measuredin vivoaccording to the protocols established in this work, and should be accounted for while setting the stimulation parameters for clinical applications including for chronic applications.