Introduction: High variability between individuals (i.e., interindividual variability) in response to transcranial direct current stimulation (tDCS) has become a commonly reported issue in the tDCS literature in recent years. Inherent genetic differences between individuals have been proposed as a contributing factor to observed response variability. This study investigated whether tDCS interindividual variability was genetically mediated. Methods: A large sample size of 61 healthy males received cathodal tDCS (c-tDCS) and sham-tDCS of the primary motor cortex at 1 mA and 10 min via 6 × 4 cm active and 7 × 5 cm return electrodes. Corticospinal excitability (CSE) was assessed via 25 single-pulse transcranial magnetic stimulation motor-evoked potentials (MEPs). Intracortical inhibition was assessed via twenty-five 3 msec interstimulus interval (ISI) paired-pulse MEPs, known as short-interval intracortical inhibition (SICI). Intracortical facilitation (ICF) was assessed via twenty-five 10 msec ISI paired-pulse MEPs. Gene variants encoding for excitatory and inhibitory neuroreceptors were determined via saliva samples. Predetermined thresholds and statistical cluster analyses were used to subgroup individuals. Results: Two distinct subgroups were identified, "responders" reducing CSE following c-tDCS and "nonresponders" showing no reduction or even increase in CSE. Differences in CSE between responders and nonresponders following c-tDCS were not explained by changes in SICI or ICF. Conclusions: No significant relationships were reported between gene variants and interindividual variability to c-tDCS, suggesting that the chosen gene variants did not influence the activity of the neuroreceptors involved in eliciting changes in CSE in responders following c-tDCS. In this largest c-tDCS study of its kind, novel insights were reported into the contribution genetic factors may play in observed interindividual variability to c-tDCS. Impact statement This study adds insight into the issue of interindividual variability to c-tDCS. It highlights not all individuals respond to c-tDCS similarly when exposed to the same stimulus parameters. This disparity in response to c-tDCS between individuals does not appear to be genetically mediated. For c-tDCS to progress to large-scale clinical application, reliability, predictability and reproducibility are essential. Systematically investigating factors contributing to interindividual variability take steps towards this progress the c-tDCS field towards the potential development of screening tools to determine clinical suitability to c-tDCS to ensure its application in those who may benefit the most.
Keywords: N-methyl-d-aspartic acid; corticospinal excitability; gamma-aminobutyric acid; interindividual variability; single-nucleotide polymorphism.