Are we really targeting and stimulating DLPFC by placing tES electrodes over F3/F4?

Background: Most transcranial electrical stimulation (tES) clinical trials place target electrodes over DLPFC based on the assumption that it would mainly stimulate the underlying brain region. Here, we assessed delivered electric fields (EF) using a symmetric and asymmetric DLPFC stimulation montage to identify additional prefrontal regions that are inadvertently targeted beyond DLPFC. Methods: Head models were generated from the human connectome project database's T1+T2-weighted MRIs of 80 healthy adults. Two common DLPFC montages (symmetric: F4/F3, asymmetric: F4/Fp1 with 5x7cm electrodes, 2mA intensity) were simulated. Averaged EF was extracted from (1) the center of the target electrode (F4), and (2) the top 1% of voxels that showed the strongest EF in individualized EF maps. Inter-individual variabilities were quantified with standard deviation (SD) of EF peak location and value. These steps were replicated with 66 participants with methamphetamine use disorder (MUD) as an independent clinical population. Results: In the healthy adults, 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). Group-level location for EF peaks in MNI space was located in medial-frontopolar cortex, such that individualized EF peaks were placed in a cube with a volume of symmetric/asymmetric: 29cm3/46cm3. Similar results (with slight between-group differences) were found for MUDs that highlighted the role of the medial frontopolar cortex in both healthy and clinical populations. Conclusions: We highlighted that in common DLPFC tES montages, DLPFC was not maximally targeted and the frontopolar area was the area that received the highest EFs. Considering inter-individual and inter-groups variability, we specifically recommended that the frontopolar role should be considered as a potential mechanism underlying the clinical efficacy of DLPFC stimulation.