Interaction of BDNF and COMT Polymorphisms on Paired-Associative Stimulation-Induced Cortical Plasticity

Abstract

The common single-nucleotide polymorphism (SNP) brain-derived neurotrophic factor (BDNF) valine-to-methionine substitution at codon 66 (Val66Met) has been associated with differences in memory functions and cortical plasticity following brain stimulation. Other studies could not confirm these results, though, and potential interactions of BDNF carrier status with other learning-relevant SNPs are largely unknown. The present study aimed to evaluate the effects of BDNF Val66Met genotype on paired associative stimulation (PAS)-induced motor cortex plasticity, while additionally taking catechol-O-methyltransferase (COMT) Val158Met and kidney and brain (KIBRA) rs17070145 carrier status into account. Therefore, a cohort of 2 ϫ 16 age-and education-matched healthy young females underwent transcranial magnetic stimulation using an excitatory PAS 25 protocol to induce cortical plasticity. Cognitive performance was assessed using implicit grammar-and motor-learning tasks and a detailed neuropsychological test battery. While BDNF carrier status alone did not significantly influence PAS-induced cortical plasticity, we found a significant BDNF ϫ COMT interaction, showing higher plasticity immediately following the PAS 25 protocol for the BDNF Val/Val vs Met genotype in COMT Met homozygotes only (ANOVA, p ϭ 0.027). A similar advantage for this group was noted for implicit grammar learning (ANOVA, p ϭ 0.021). Accounting for KIBRA rs17070145 did not explain significant variance. Our findings for the first time demonstrate an interaction of BDNF by COMT on human cortical plasticity. Moreover, they show that genotype-related differences in neurophysiology translate into behavioral differences. These findings might contribute to a better understanding of the mechanisms of interindividual differences in cognition.

Dosage-Dependent Effect of Dopamine D2 Receptor Activation on Motor Cortex Plasticity in Humans

“…Third, dopaminergic medication seems to enhance interindividual variability. This is probably caused by the dosage-dependent modulatory effect of dopamine, which could in combination with genetic polymorphisms (Wong et al, 2000;Witte and Flöel, 2012;Witte et al, 2012;Kristin et al, 2013) and differences of resorption of the substance, which we both did not explore, result in interindividually different activation of D 2 receptors despite identical dosages. Finally, blinding might have been compromised in one subject for whom the respective session had to be cancelled as a result of vomiting after the high dosage of bromocriptine.…”

Imaging human brain networks to improve the clinical efficacy of non-invasive brain stimulation

“…However, it is reasonable to assume that these factors also contribute to the variability of brain stimulation paradigms in other, non-motor regions of the brain. The causes of this variability are currently not fully understood, but most likely include factors such as genetics (Witte et al, 2012), age (Todd et al, 2010), history of previous cortical activity (Sale and Mattingley, 2013), time of day of stimulation (Sale et al, 2007; A c c e p t e d M a n u s c r i p t Sale et al, 33 Sale et al, 2008), and cognitive factors such as attention (Kamke et al, 2012;Kamke et al, 2014). By better understanding the factors that mediate an individual's response to NIBS, it should be easier to screen clinical groups to identify those most likely to respond.…”

Does transcranial direct current stimulation enhance cognitive and motor functions in the ageing brain? A systematic review and meta- analysis

“…There are a number of other genetic polymorphisms that may influence the response to brain stimulation protocols and research into their effect in isolation and in interaction with other genes is just beginning (Witte et al, 2012).…”