Introduction: Transcranial direct current stimulation (tDCS) of prefrontal cortex (PFC) regions is a widely used experimental intervention in neuroscience as well as a novel therapeutic approach in psychiatry. However, its mechanistic understanding is still under investigation. In this conceptual study, we combined online tDCS, MR spectroscopy (MRS), resting state functional MRI connectivity (rsfcMRI) and computational modeling of tDCS induced electric fields in order to investigate the effect of prefrontal tDCS on brain metabolites and resting-state functional connectivity in relation to the respective modeled efield. Methods: In a double-blind cross-over design, 19 subjects (11 women, mean age 23) underwent both active and sham tDCS (anode – F3, cathode – F4) in randomized sequential order. MRS was acquired before, during, and after prefrontal tDCS to quantify glutamate (Glu), Glu + glutamine (Glx) and gamma-aminobutyric acid (GABA) concentration. RsfcMRI measurements were run before and after the stimulation. Additionally, efield distribution was modelled to explore relations between efield, rsfcMRI and MRS. Results: A reduction of Glu concentration during active tDCS was observed in the investigated area of the right dorsolateral PFC located under the cathode. Significant modulation of network connectivity from this area to the whole brain was observed. Additionally, we found large variations in electrical field distribution
across individuals with varying outreach in the MRS target region. Investigation of gender specific responses showed stronger tDCS effects in women. Conclusion: Glu under the cathode during prefrontal tDCS may partially depend on gender and intensity of the tDCS induced efield. This is in line with a very recently published study (Antonenko et al., 2019). For future studies multivoxel MRS with online tDCS including computational efield modeling could be a promising opportunity for a deeper mechanistic understanding of tDCS induced effects in the human brain.