Background: Temporal interference stimulation (TIS) has been proposed as a non-invasive focal and steerable deep brain stimulation method. However the mechanisms underlying experimentally observed TIS effects are unknown and prior simulation studies have limitations in the representations of the TIS electric field (E-field) and cerebral neurons. Objective: To examine the E-field and neural response characteristics for TIS and other transcranial alternating current stimulation modalities. Methods: We simulated a range of stimulation parameters in layer 5 pyramidal neurons including different orientations frequencies amplitude ratios amplitude modulation and phase difference of the E-fields and obtained thresholds for both activation and block. Results: TIS has unique E-field characteristics. At the target region in the cortex where the two E-fields have similar amplitudes TIS generates an amplitude-modulated total E-field. The TIS E-field also exhibits rotation where the E-field orientations are not aligned which generally co-localizes with the target. TIS activation thresholds are similar to high-frequency stimulation with or without modulation and/or rotation (75–230 V/m). Outside the target region the TIS E-field is dominated by the high-frequency carrier with minimal amplitude modulation and/or rotation and it is less effective at activation and more effective at block. TIS creates block for some combinations of E-field orientations and amplitude ratios at very high amplitudes (>1700 V/m) whereas amplitude modulated single-carrier high-frequency stimulation cannot achieve similar effects regardless of orientation. Conclusion: All observed effects occurred at E-field strengths that are too high to be delivered tolerably through scalp electrodes suggesting limited significance of suprathreshold TIS.
