Can genetic polymorphisms predict response variability to anodal transcranial direct current stimulation of the primary motor cortex?

Abstract

Genetic mediation of cortical plasticity and the role genetic variants play in previously observed response variability to transcranial direct current stimulation (tDCS) have become important issues in the tDCS literature in recent years. This study investigated whether inter‐individual variability to tDCS was in‐part genetically mediated. In 61 healthy males, anodal‐tDCS (a‐tDCS) and sham‐tDCS were administered to the primary motor cortex at 1 mA for 10‐min via 6 × 4 cm active and 7 × 5 cm return electrodes. Twenty‐five single‐pulse transcranial magnetic stimulation (TMS) motor evoked potentials (MEP) were recorded to represent corticospinal excitability (CSE). Twenty‐five paired‐pulse MEPs were recorded with 3 ms inter‐stimulus interval (ISI) to assess intracortical inhibition (ICI) via short‐interval intracranial inhibition (SICI) and 10 ms ISI for intracortical facilitation (ICF). Saliva samples were tested for specific genetic polymorphisms in genes encoding for excitatory and inhibitory neuroreceptors. Individuals were sub‐grouped based on a pre‐determined threshold and via statistical cluster analysis. Two distinct subgroups were identified, increases in CSE following a‐tDCS (i.e. Responders) and no increase or even reductions in CSE (i.e. Non‐responders). No changes in ICI or ICF were reported. No relationships were reported between genetic polymorphisms in excitatory receptor genes and a‐tDCS responders. An association was reported between a‐tDCS responders and GABRA3 gene polymorphisms encoding for GABA‐A receptors suggesting potential relationships between GABA‐A receptor variations and capacity to undergo tDCS‐induced cortical plasticity. In the largest tDCS study of its kind, this study presents an important step forward in determining the contribution genetic factors play in previously observed inter‐individual variability to tDCS.

Single gene polymorphisms as a predictor of noninvasive brain stimulation effectiveness (commentary on Pellegrini et al, 2021)

“…This recent work does not include any genotyping, but it does provide the simulation of the applied tDCS montage and the resulting differences in cortical excitability. While no significant effect of the anodal tDCS on the MEP amplitude was found in Pellegrini et al (2021c), a very significant effect was found in the present study (Pellegrini et al, 2021a). The authors do not comment on this discrepancy.…”

“…And their answer is “Yes” if we find a way to personalize it. A very effective way to do that would be through usage of biomarkers (like gene polymorphisms) and this is where the paper by Pellegrini et al (2021a) attempts to give its contribution.…”

“…The paper by Pellegrini et al (2021a) joins a long list of experiments performed in order to establish an association between gene polymorphisms and the effects of tDCS. While most of the previous findings relate to the BDNF and catechol‐O‐methyltransferase (COMT) genes, others like NMDA and GABA receptors were also explored (see Chhabra et al, 2016, for a detailed review).…”

“…Further comparison between the results presented in these two papers raises questions as to how statistical analyses were performed. Because the two papers are identical in every aspect except the type of applied tDCS stimulation, it is hard to understand why the authors excluded three SNPs (GRIN2B rs1805247, GABRA1 rs6883877 and GABRA2 rs511310) from the cathodal study (Pellegrini et al, 2021b) due to the “disproportionate sample‐sizes”, but kept them in the anodal study (Pellegrini et al, 2021a). The decision to exclude these SNPs was a correct one and should have also been applied to the BDNF SNP for the same reason.…”

A Future of Current Flow Modelling for Transcranial Electrical Stimulation?

“…On the one hand, we know that tES can alter GABA concentration, even in unstimulated brain regions [70,71], and that this directly relates to performance in a behavioural task [72][73][74]. We also know that neurochemical 'state' determines the capacity to undergo tES-induced cortical plasticity [45,75,76]. For example, the relative concentrations of both GABA and glutamate in prefrontal cortex determine the impact of tES on performance in a response to a selection task [77].…”