Genetic polymorphisms do not predict inter-individual variability to cathodal transcranial direct current stimulation of the primary motor cortex

Abstract

High variability between individuals (i.e. inter-individual 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 has been proposed as a contributing factor to observed response variability. This study investigated whether tDCS inter-individual variability was genetically mediated. A large sample-size of sixty-one healthy males received cathodal-tDCS (c-tDCS) and sham-tDCS, of the primary motor cortex at 1mA and 10-minutes via 6x4cm active and 7x5cm return electrodes. Corticospinal excitability (CSE) was assessed via twenty-five single-pulse transcranial magnetic stimulation motor evoked potentials (MEP).Intracortical inhibition (ICI) was assessed via twenty-five 3ms inter-stimulus interval (ISI) pairedpulse MEPs, known as short-interval intracortical inhibition (SICI). Intracortical facilitation (ICF) was assessed via twenty-five 10ms ISI paired-pulse MEPs. Gene variants encoding for excitatory and inhibitory neuroreceptors were determined via saliva samples. Pre-determined thresholds and statistical cluster analyses were used to subgroup individuals. Two distinct subgroups were identified, 'responders' reducing CSE following c-tDCS and 'non-responders' showing no reduction or even increase in CSE. Differences in CSE between responders and non-responders following c-tDCS were not explained by changes in SICI or ICF. No significant relationships were reported between gene variants and inter-individual variability to c-tDCS suggesting 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 inter-individual variability to c-tDCS. Key WordsCorticospinal excitability, Gamma-aminobutyric acid, Inter-individual variability, N-methyl-daspartic acid, Single nucleotide polymorphism This study therefore aimed to be the first of its kind to investigate the relationship between NMDA and GABA receptor gene variants and inter-individual variability to c-tDCS. In a large sample-size, this study also aimed to investigate the predictive value of the selected gene variants for response to c-tDCS. The significance of this study will be its novelty in investigating c-tDCS, and its largescale nature which will facilitate meaningful subgroup statistical analysis, thus increasing the power and impact of the research findings. This may provide insight into future studies investigating the application of c-tDCS whereby reductions in cortical excitability and CSE is desired such as in excitotoxic neurological populations such as Epilepsy and those prone to seizures.We hypothesised there would be an association and predictive capacity between the selected gene variants and c-tDCS response. We hypothesised normal expression of genes encoding for GABA receptors would be associated...