Energy-dependent cortical injury thresholds in high-frequency transcortical electrical stimulation: a biophysical study in a rat model

Abstract The biophysical determinants of cortical tissue injury during brief, high-frequency transcortical electrical stimulation remain incompletely understood. Traditional safety criteria derived from chronic, low-frequency paradigms emphasize total charge, but whether charge or stimulation energy is the primary predictor of injury under high-frequency conditions—such as those used for intraoperative motor evoked potential (MEP) monitoring—is unclear. Thirty-two Sprague-Dawley rats (8 groups of 4) received monophasic anodal transcortical pulse trains with varying current, pulse duration, repetition number, and interstimulation interval. Maximum cortical lesion depth was measured histologically, and the contributions of total charge (Q = I × t) and relative stimulation energy (W ∝ I 2 t) were dissociated through controlled group comparisons and multiple linear regression. Higher stimulation current ( p = 0.04) and greater repetition number ( p = 0.005) significantly increased lesion depth. Multiple regression identified total stimulation energy as the only significant independent predictor ( p = 0.008), whereas total charge was not ( p = 0.677). With equivalent total charge, higher-energy stimulation tended to produce deeper lesions (209 ± 67 vs. 125 ± 101 μm, p = 0.25); when total energy was equalized despite a 2.5-fold difference in total charge, no detectable difference in lesion depth was observed ( p = 1.0). Under high-frequency conditions, cortical injury depth appears to be more strongly associated with total energy deposition than with total charge alone, consistent with biophysical mechanisms involving resistive heating and electrolytic processes at the electrode–tissue interface. These findings provide a mechanistic framework for understanding electrical tissue injury under MEP-relevant stimulation regimes.