Modeling iACS to target the hippocampus and SVZ

To assess the plausibility of using iACS to stimulate the SVZ and hippocampus, we used a finite element method (FEM) to approximately estimate the distribution of currents and electric fields in a three-dimensional mouse brain model (Fig. 1F). Our model is based on a 3D C57BL/6 mouse brain atlas built from MRI and Nissl histology, which consists of 39 different brain segments (Fig. 1F) [43]. We assigned the electrical conductivity and relative permittivity (at 40 Hz, stimulation frequency used in our study) to these segments [44] and rendered the 3D model so it contains a total of 189 × 236 × 152 voxels with voxel resolutions ~ 100 × 100 × 100 μm³. We used the Sim4Life platform (Zurich MedTech AG) to perform a quasi-electrostatic FEM simulation to calculate the electric current distribution in the brain model. The simulation calculates the ohmic current, which is suitable for the stimulation frequency used in our study (40 Hz), as the displacement current can be considered negligible.

Intracranial AC stimulation and the estimated current distribution. A–C Two small stainless steel screws were implanted in the skull at anterior-posterior (AP) = − 2 mm and medial-lateral (ML) = 4 (left and right) mm to the bregma. D, E The iACS was delivered through the screw electrodes on the dura. The mouse brain atlas was quoted from ref. [42]. F The three-dimensional (3D) brain model, based on a C57BL/6 mouse brain atlas built from MRI and Nissl histology, which consists of 39 different brain segments (in different colors, F1). F2–F4 The top (F2), front (F3), and side (F4) views of the 3D brain model with electrodes (white circles) on both hemispheres. F5 The dura layer of the 3D brain model. F6 The cerebral spinal fluid layer under the dura. F7 The white matter of the 3D brain model in color (other brain regions were shown in gray shade). F8 The gray matter of the 3D brain model in color (other brain regions were shown in gray shade). F9 The lateral ventricle of the 3D brain model in pink (other brain regions were shown in gray shade). F10 The hippocampus of the 3D brain model in orange (other brain regions were shown in gray shade). G Computer simulation was used to estimate the current densities (G1–G4, A/m²) and electric field strengths (G5–G8, V/m) in different brain regions, thus guide positioning of electrodes that would likely result in desirable and safe current and electric field distributions at sites of neurogenesis, including the subventricular zone (SVZ) and the hippocampus. The strongest currents and electric fields originate from the electrodes (circles in G) and flow into the brain with gradually decreasing density (G1, G3, G5, G7). The current of ~ 10 A/m² (G3) and electric fields of ~ 10–50 V/m (G7) would reach the hippocampus. The strong current and electric field at the SVZ (~ 1–10 A/m², ~ 10 V/m) are presumably due to interface of high conductivity, relatively low permittivity of CSF and less conductive, higher permittivity brain parenchyma (G2, G4, G6, G8)

Modeled electrodes were placed over the dura through a craniotomy hole (Fig. 1E), because electrodes placed on the dura have better control of the electric field/current delivery than electrodes placed over the skin and skull [45, 46]. As the available mouse atlas does not contain cerebral spinal fluid (CSF) layer surrounding the brain and the dura, we added a dura layer of 300 μm (Fig. 1F5) and CSF 43 μm (Fig. 1F6) [42]. Multiple simulations of the iACS current were calculated using electrodes placed at different positions in order to identify electrode positions that would maximally stimulate the SVZ (Fig. 1F9) and hippocampus (Fig. 1F10).