## 4 Discussion  
TI stimulation has emerged as an effective noninvasive electrical stimulation modality for modulating brain tissues. Nonetheless, its application has recently extended to the peripheral nervous system in which the surrounding tissue composition is anatomically much simpler than that of the brain. Also, there is no low conductive tissue, such as the skull in the vicinity; thus, current penetration to the deeper-lying tissues, such as nerves, is more efficient. In this regard, TI current-based tibial nerve stimulation has been recently proposed, but its applicability was evaluated via limited in-silico studies with a small number of human models; thus, the anatomical differences in individuals have yet to be attempted. Therefore, through a large-scale in-silico study using MR image-driven human leg phantoms, we evaluated the effectiveness of TI current-based tibial nerve stimulation as an OAB-treating neuromodulation technique and develop the TI field optimization framework that can overcome the individual anatomical differences to focus the induced fields on the tibial nerve. TI stimulation requires two pairs of electrodes, and input currents and physical placement of the electrodes can largely affect the induced field distribution. Therefore, an optimal arrangement of those parameters, such as currents and placement of electrodes, is critical to overcoming the individual anatomical differences, and we developed a framework to determine the optimal stimulation condition using the individual phantom models driven from the MR images. As shown in Figure 3, the optimized placement of parallel pairs of electrodes resulted in 87 times higher PR value than the worst placement of parallel \begin{table}
\begin{tabular}{c c c c} \hline \hline
**Subject ID** & **Electrode Pair** & **Current Adjustment** \\ \hline
0A/7 CE3A9878D & E1: 3, 16 & E2: 10, 19 & E1: 0.6 & E2: 1.4 \\
0 BB634E25B39 & E1: 2, 14 & E2: 4, 16 & E1: 1.5 & E2: 0.5 \\
0C2 CD6A715D9 & E1: 3, 15 & E2: 5, 17 & E1: 0.9 & E2: 1.1 \\  
61F9C73 & E1: 7, 18 & E2: 10, 23 & E1: 1.4 & E2: 0.6 \\ AFA8C6F48087 & E1: 10, 22 & E2: 12, 24 & E1: 1.2 & E2: 0.8 \\ BDBD4C7F4443 & E1: 3, 13 & E2: 10, 23 & E1: 1.3 & E2: 0.7 \\ EB27F9C7 CA47 & E1: 10, 21 & E2: 12, 24 & E1: 0.9 & E2: 1.1 \\ \hline \hline \end{tabular}
\end{table} 
Table 4: Optimization parameter settings for intensity opt TI. electrodes, indicating that the field targeting ability significantly depends on the position of the electrode pair. Thus, as suggested by previous studies, optimizing the position of the electrodes when performing TI stimulation on the tibial nerve is important [18; 20; 23]. In the case of cross-opt TI, not only parallel pairs of electrodes but also random pairs are allowed. With such a method allowing for random selection of electrode pairs, improved targeting capability can be expected due to the greater number of possible electrode combinations. Comparisons of parallel opt TI and cross opt TI revealed the PR value of cross opt TI was higher than that of parallel opt TI. Thus, when an arbitrary electrode pair selection is allowed and the optimization algorithm is applied, a higher targeting ability is realized compared to when only a parallel pair combination is applied. Intensity opt TI is the setting with the highest targeting ability when both the electrode position adjustment and current adjustment are considered. Comparing the Cross opt TI method with the Intensity opt TI method, the PR value of Intensity opt TI was higher. Our results suggest that current adjustment is also a significant factor in enhancing the targeting ability in the optimization of TI stimulation. Furthermore, we found that both the electrode position and current intensity must be considered when manually optimizing TI stimulation focusing. Therefore, an optimization approach using both the free selection of electrode pairs and current adjustment proved to be the most effective method. In addition, we analyzed the anatomical factors that must be considered when performing TI optimization.