P 29. BDNF val66met polymorphism influences the time course of changes in corticospinal excitability induced by paired associative and transcranial direct current stimulation

Abstract

It is widely appreciated that brain-derived neurotrophic factor (BDNF) is released in an activity dependent manner within the brain, and that it plays a key role in regulating synaptic plasticity and long-term potentiation (LTP). A single nucleotide polymorphism (SNP) arises at nucleotide 196 of the eponymous gene in humans. This gives rise to a valine to methionine substitution at codon 66 of the precursor protein. When assessed in animal models, the presence of this substitution is associated with impaired intracellular transport and reduced capacity for LTP. Differences between met carriers and val homozygotes have been reported in studies investigating the plasticity of human motor cortex in response to various forms of brain stimulation. Those who are homozygous for the val allele show elevations in corticospinal excitability following paired associative stimulation (PAS) ( Cirillo et al., 2012 ) and “theta burst” repetitive transcranial magnetic stimulation (rTMS) ( Cheeran et al., 2008 ), that are larger than those exhibited by individuals with a met allele. In contrast, Antal et al. (2010) reported that met carriers show an accentuated response to transcranial direct current stimulation (tDCS). Given the clinical potential of brain stimulation techniques, there is a pressing need to establish the basis of these contrarieties, and the generality of effects attributable to BDNF genotype. In the present study, we focused on corticospinal projections to muscles of the forearm that are of particular significance in rehabilitation following stroke. Consideration was given to two forms of brain stimulation-PAS and tDCS that putatively have utility in this context. A total of 56 participants (29 Female) aged 19–32 (mean ± SD: 22.31 ± 3.42 years) underwent PAS. There were 53 participants (30 Female) aged between 18 and 32 (mean ± SD: 22.35 ± 3.44) who took part in the tDCS condition. PAS consisted of a train of electrical stimulation (1 ms pulse width, 10 Hz, 500 ms duration) delivered to the right Flexor Carpi Radialis (FCR) motor point, followed 25 ms later by a TMS pulse delivered to M1. This was repeated every 10 s for 30 min (total 180 pairs). Anodal 1 mA tDCS was delivered to M1 for 30 min. Motor evoked potentials (MEPs) in response to TMS of the target area were obtained on prior to the intervention, and at 0, 10, 20 and 30 min following the cessation of stimulation. With respect to FCR, val homozygotes exhibited increased corticospinal excitability following tDCS that emerged after 10 min and remained elevated thereafter. In met carriers there was a transient increase in MEP amplitude that peaked 10 min post-intervention. The val homozygotes exhibited a qualitatively similar pattern of response to PAS, whereby increases in corticospinal excitability were delayed. Although weaker overall, the elevations of MEP amplitude exhibited by met carriers were larger immediately following the cessation of stimulation than subsequently. In relation to ECR, the profile of response to tDCS was similar to that manifested in FCR. The val homozygotes exhibited an immediate and sustained elevation in ECR MEP amplitude following PAS. No such changes were present for met carriers. In summary, these findings suggest that met carriers respond transiently, albeit weakly, to brain stimulation. Responses to tDCS are more prominent than those to PAS. Val homozygotes exhibit responses to both forms of stimulation that tend to increase in magnitude over 30 min post-intervention.