Exploring the Effects of Prefrontal Transcranial Direct Current Stimulation on Brain Metabolites: A Concurrent tDCS-MRS Study.

Transcranial Direct Current Stimulation (tDCS) is a non-invasive brain stimulation technique used to modulates cortical brain activity. However, its effects on brain metabolites within the dorsolateral prefrontal cortex (DLPFC), a crucial area targeted for brain stimulation in mental disorders, remain unclear. This study aimed to investigate whether prefrontal tDCS over the left and right DLPFC modulates levels of key metabolites, including gamma-aminobutyric acid (GABA), glutamate (Glu), glutamine/glutamate (Glx), N-acetylaspartate (NAA), near to the target region and to explore potential sex-specific effects on these metabolite concentrations. A total of 41 healthy individuals (19 female, M_age = 25 years, SD = 3.15) underwent either bifrontal active (2 mA for 20 min) or sham tDCS targeting the left (anode: F3) and right (cathode: F4) DLPFC within a 3 Tesla MRI scanner. Magnetic resonance spectroscopy (MRS) was used to monitor neurometabolic changes before, during, and after 40 min of tDCS, with measurements of two 10-min intervals during stimulation. A single voxel beneath F3 was used for metabolic quantification. Results showed a statistically significant increase in Glx levels under active tDCS compared to the sham condition, particularly during the second 10-min window and persisting into the post-stimulation phase. No significant changes were observed in other metabolites, but consistent sex differences were detected. Specifically, females showed lower levels of NAA and GABA under active tDCS compared to the sham condition, while no significant changes were observed in males. E-field modeling showed no significant differences in field magnitudes between sexes, and the magnitude of the e-fields did not correlate with changes in Glx levels between active and sham stimulation during the second interval or post-stimulation. This study demonstrates that a single session of prefrontal tDCS significantly elevates Glx levels in the left DLPFC, with effects persisting post-stimulation. However, the observed sex differences in the neurochemical response to tDCS were not linked to specific stimulation intervals or variations in e-field magnitudes, highlighting the complexity of tDCS effects and the need for personalized neuromodulation strategies.