The Impact of Electrode Placement and Electrical Conductivity Uncertainties on Temporal Interference Stimulation

Abstract Temporal interference stimulation (TIS) promises deeper and more selective neuromodulation, yet predictions remain sensitive to uncertainties in electrode setup and head modeling. We investigate the impact of coregistration error (CE) of the volume conductor and the head, electrode placement uncertainty (EP), and tissue conductivity uncertainty (CU) on the electric field generated by TIS. The stochastic model aggregates CE, EP, and CU into nineteen random variables and is evaluated for a deep target in the left hippocampus and a superficial target in the motor cortex. The uncertainty and sensitivity analysis of the maximal modulation envelope of the electric field is based on an adaptive polynomial chaos expansion (PCE). Spatial statistics show that the mean of the electric field remains focalized over the regions of interest (ROIs), whereas the standard deviation is concentrated in targeted regions, indicating that uncertainty perturbs the electric field magnitude more than its focality. Variance decomposition reveals a clear hierarchy: CU is the main contributor to field variability, EP has a modest influence, and CE is essentially negligible within the considered ranges. Probability-density estimates of the mean strength inside and outside ROIs demonstrate separated distributions, confirming strong dose selectivity for both deep and superficial targets, while the relative difference measure (RDM) confirms that the spatial pattern of the TI field stays close to the reference configuration, indicating that uncertainty rescales the field rather than relocating its focal point. Generalization across four individualized head models spanning a range of head sizes confirms that the variance hierarchy CU > EP > CE and the dominance of a single electrode within EP are preserved across anatomies. Overall, within realistic modeling and setup uncertainties, TIS targeting appears robust when using state-of-the-art MRI-based electrode localization. The analysis identifies insufficient knowledge of tissue conductivities as the primary limitation for further improving the reliability of electric field predictions in TIS.