A common polymorphism in the brain-derived neurotrophic factor gene (BDNF) modulates human cortical plasticity and the response to rTMS

Abstract

The brain-derived neurotrophic factor gene (BDNF) is one of many genes thought to influence synaptic plasticity in the adult brain and shows a common single nucleotide polymorphism (BDNF Val66Met) in the normal population that is associated with differences in hippocampal volume and episodic memory. It is also thought to influence possible synaptic changes in motor cortex following a simple motor learning task. Here we extend these studies by using new non-invasive transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (TDCS) techniques that directly test the excitability and plasticity of neuronal circuits in human motor cortex in subjects at rest. We investigated whether the susceptibility to TMS probes of plasticity is significantly influenced by the BDNF polymorphism. Val66Met carriers were matched with Val66Val individuals and tested on the following protocols: continuous and intermittent theta burst TMS; median nerve paired associative stimulation; and homeostatic plasticity in the TDCS/1 Hz rTMS model. The response of Met allele carriers differed significantly in all protocols compared with the response of Val66Val individuals. We suggest that this is due to the effect of BNDF on the susceptibility of synapses to undergo LTP/LTD. The circuits tested here are implicated in the pathophysiology of movement disorders such as dystonia and are being assessed as potential new targets in the treatment of stroke. Thus the polymorphism may be one factor that influences the natural response of the brain to injury and disease.

Figures

Figure 1. Effect of BDNF Val66Met polymorphism on cortical excitability in response to cTBS (top row) and iTBS (bottom row)

Data are mean (+s.e.m.) peak-to-peak amplitudes of MEP. A and B plot data at all time points; C and D, the data from the 4 post-TBS sessions have been averaged to allow direct comparison of overall pre- vs post-TBS MEP amplitudes in the two groups of subjects (*P < 0.05).

Figure 2. Effect of BDNF Val66Met polymorphism on cortical excitability in response to cathodal TDCS preconditioning followed by sub-threshold 1 Hz rTMS

Data are mean (+s.e.m.) peak-to-peak MEP amplitude (*P < 0.05).

Figure 3. Effect of BDNF Val66Met polymorphism on cortical excitability in response to paired associative stimulation in the target (homotypic) abductor pollicis brevis (top row) and (heterotopic) ulnar-innervated abductor digiti minimi (bottom row)

Data are mean (+s.e.m.) peak-to-peak amplitudes of MEP. A and B plot data at all time points; C and D, the data from the 5 post-PAS sessions have been averaged to allow direct comparison of overall pre- vs post-PAS MEP amplitudes in the two groups of subjects (*P < 0.05).