Abstract
Objective: Transcutaneous electrical stimulation aims to restore sensation and function in individuals with sensory or motor deficits. However, limited selectivity and unintended nerve recruitment often result in discomfort. Temporal interference (TI) stimulation has been proposed as a novel approach to non-invasive nerve stimulation, hypothesising that low-frequency modulation of kilohertz carriers reduces activation thresholds. Prior studies have produced conflicting results regarding comfort in kilohertz-frequency stimulation, and the practical applicability of TI remains unclear. This study addresses these gaps by systematically analysing the role of depth of modulation in activation thresholds and comfort, focusing on peripheral nerves and clinically relevant stimulation levels.

Approach: This study uses a dual-method approach combining computational and psychophysical experiments targeting the median nerve. Computational modelling involved nine MRI-informed finite element models to account for anatomical variability and biophysical neural activation predictions using NEURON. Psychophysical experiments with 19 participants determined stimulation thresholds and comfort levels. Statistical analysis using the Friedman test and Bonferroni correction assessed the impact of carrier and beat frequencies, and depth of modulation on activation thresholds and comfort.

Main results: The results showed that the activation thresholds did not vary with the depth of modulation, challenging the core assumption underlying temporal interference stimulation. Despite that, comfort significantly increased with carrier frequencies as low as 500 Hz, with no further significant changes at higher frequencies. Computational modelling results showed an association between increased comfort and asynchronous nerve activation patterns, providing a possible explanation for the observed improvement in comfort. 

Significance: By challenging a core assumption of TI stimulation, this study shifts the focus from threshold modulation to optimising comfort in peripheral nerve stimulation. These findings establish a foundation for developing kilohertz-frequency stimulation protocols prioritising user comfort, particularly in applications such as functional electrical stimulation for rehabilitation or sensory feedback for prostheses. 
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