Responses of Model Cortical Neurons to Temporal Interference Stimulation and Related Transcranial Alternating Current Stimulation Modalities

ObjectiveTemporal interference stimulation (TIS) was proposed as a non-invasive, focal, and steerable deep brain stimulation method. However, the mechanisms underlying experimentally-observed suprathreshold TIS effects are unknown, and prior simulation studies had limitations in the representations of the TIS electric field (E-field) and cerebral neurons. We examined the E-field and neural response characteristics for TIS and related transcranial alternating current stimulation modalities. ApproachUsing the uniform-field approximation, we simulated a range of stimulation parameters in biophysically realistic model cortical neurons, including different orientations, frequencies, amplitude ratios, amplitude modulation, and phase difference of the E-fields, and obtained thresholds for both activation and conduction block. Main resultsFor two E-fields with similar amplitudes (representative of E-field distributions at the target region), TIS generated an amplitude-modulated total E-field. Due to the phase difference of the individual E-fields, the total TIS E-field vector also exhibited rotation where the orientations of the two E-fields were not aligned (generally also at the target region). TIS activation thresholds (75-230 V/m) were similar to those of high-frequency stimulation with or without modulation and/or rotation. For E-field dominated by the high-frequency carrier and with minimal amplitude modulation and/or rotation (typically outside the target region), TIS was less effective at activation and more effective at block. Unlike amplitude-modulated high-frequency stimulation, TIS generated conduction block with some orientations and amplitude ratios of individual E-field at very high amplitudes of the total E-field (>1700 V/m). SignificanceThe complex 3D properties of the TIS E-fields should be accounted for in computational and experimental studies. The mechanisms of suprathreshold cortical TIS appear to involve neural activity block and periodic activation or onset response, consistent with computational studies of peripheral axons. These phenomena occur at E-field strengths too high to be delivered tolerably through scalp electrodes and may inhibit endogenous activity in off-target regions, suggesting limited significance of suprathreshold TIS.