Are we really targeting and stimulating DLPFC by placing transcranial electrical stimulation (tES) electrodes over F3/F4?

In many clinical trials involving transcranial electrical stimulation (tES), target electrodes are typically placed over DLPFC with the assumption that this will primarily stimulate the underlying brain region. However, our study aimed to evaluate the electric fields (EF) that are actually delivered and identify prefrontal regions that may be inadvertently targeted in DLPFC tES. Head models were generated from the Human Connectome Project database's T1 + T2-weighted MRIs of 80 healthy adults. Two common DLPFC montages were simulated; symmetric-F4/F3, and asymmetric-F4/Fp1. Averaged EF was extracted from (1) the center of the target electrode (F4), and (2) the top 1% of voxels showing the strongest EF in individualized EF maps. Interindividual variabilities were quantified with the standard deviation of EF peak location/value. Similar steps were repeated with 66 participants with methamphetamine use disorder (MUDs) as an independent clinical population. In healthy adults, the group-level location of EF peaks was situated in the medial-frontopolar, and the individualized EF peaks were positioned in a cube with a volume of 29 cm3 /46 cm3 (symmetric/asymmetric montages). EFs in the frontopolar area were significantly higher than EF "under" the target electrode in both symmetric (peak: 0.41 ± 0.06, F4:0.22 ± 0.04) and asymmetric (peak: 0.38 ± 0.04, F4:0.2 ± 0.04) montages (Heges'g > 0.7). Similar results with slight between-group differences were found in MUDs. We highlighted that in common DLPFC tES montages, in addition to interindividual/intergroup variability, the frontopolar received the highest EFs rather than DLPFC as the main target. We specifically recommended considering the potential involvement of the frontopolar area as a mechanism underlying the effectiveness of DLPFC tES protocols.