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 sixty-one healthy males, anodal-tDCS (a-tDCS) andsham-tDCS were administered to the primary motor cortex at 1mA for 10-minutes via 6x4cm active and 7x5cm 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 3ms inter-stimulus interval (ISI) to assess intracortical inhibition (ICI) via short-interval intracranial inhibition (SICI) and 10ms ISI for intracortical facilitation (ICF). Saliva samples 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.

Genetic Polymorphisms Do Not Predict Interindividual Variability to Cathodal Transcranial Direct Current Stimulation of the Primary Motor Cortex

“…In this current study, an association approaching significance, that-being those with GABRA3 gene variants less likely to respond to c-tDCS as expected with reductions in CSE, suggests a potential reduced capacity for GABAergic inhibitory regulation in individuals categorised as c-tDCS non-responders. This potential relationship is consistent with recently published results suggesting a link between variants in genes that encode for GABA receptors and an increased likelihood of responding to excitatory a-tDCS with increases in CSE (Pellegrini et al, 2020a).…”

“…In conjunction with a previously published study (Pellegrini et al, 2020a), this study is the first and largest of its kind to investigate inter-individual variability to c-tDCS and the involvement of specific variants in genes that encode for key regulators along excitatory and inhibitory cortical pathways. The novel findings that when all genetic variants were accounted for, a trending towards significance association exists between a GABRA3 gene variant and c-tDCS non-responder categorisation suggests a potential relationship between GABRA3 gene variants and reduced capacity for ICI and c-tDCS non-responder categorisation.…”

“…variations of other regulators of cortical plasticity. The LTP-like mechanisms of a-tDCS led a recent large-scale study to investigate the role of genetic variations in the genes that encode for N-methyl-D-aspartic acid (NMDA) receptors and gamma-Aminobutyric acid (GABA) receptors and their predictive value for a-tDCS inter-individual variability (Pellegrini et al, 2020a). Novel large-scale investigations into genetic variations and their predictive value for c-tDCS inter-individual variability are yet to be conducted in the tDCS literature.…”

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

“…Oragene-DNA self-collection kits (DNAgenotek, Ontario, Canada) were used to obtain the saliva samples. Ten genetic single nucleotide polymorphisms (SNP) were chosen based on a previous similar study investigating the role of genetic polymorphisms in inter-individual variability to tDCS (Pellegrini et al, 2020a). The ten SNPs were selected as they are involved in synaptic transmission.…”

“…However with lack of definitive conclusions on the role BDNF in LTP-like and LTD-like cortical plasticity following NIBS protocols such as tDCS (Brunoni et al, 2013;Chhabra et al, 2016;Di Lazzaro et al, 2015;Fujiyama et al, 2014;Mastroeni et al, 2013) has encouraged investigations into gene variations of other regulators of cortical plasticity. The LTP-like mechanisms of a-tDCS led a recent large-scale study to investigate the role of genetic variations in the genes that encode for N-methyl-D-aspartic acid (NMDA) receptors and gamma-Aminobutyric acid (GABA) receptors and their predictive value for a-tDCS inter-individual variability (Pellegrini et al, 2020a). Novel large-scale investigations into genetic variations and their predictive value for c-tDCS inter-individual variability are yet to be conducted in the tDCS literature.…”