The presence of a single-nucleotide polymorphism in the BDNF gene affects the rate of locomotor adaptation after stroke

Abstract

Induction of neural plasticity through motor learning has been demonstrated in animals and humans. Brain derived neurotrophic factor (BDNF), a member of the neurotrophin family of growth factors, is thought to play an integral role in modulation of central nervous system plasticity during learning and motor skill recovery. Thirty percent of humans possess a single nucleotide polymorphism on the BDNF gene (Val66Met), which has been linked to decreased activity dependent release of BDNF. Presence of the polymorphism has been associated with altered cortical activation, short term plasticity and altered skill acquisition, and learning in healthy humans. The impact of the Val66Met polymorphism on motor learning post-stroke has not been explored. The purpose of this study was to examine the impact of the Val66Met polymorphism in learning of a novel locomotor task in subjects with chronic stroke. It was hypothesized that subjects with the polymorphism would have an altered rate and magnitude of adaptation to a novel locomotor walking paradigm (the split-belt treadmill), compared to those without the polymorphism. The rate of adaptation was evaluated as the reduction in gait asymmetry during the first 30 (early adaptation) and last 100 (late adaptation) strides. Twenty-seven individuals with chronic stroke participated in a single session of split-belt treadmill walking and tested for the polymorphism. Step length and limb phase were measured to assess adaptation of spatial and temporal parameters of walking. The rate of adaptation of step length asymmetry differed significantly between those with and without the polymorphism, while the amount of total adaptation did not. These results suggest that chronic stroke survivors, regardless of presence or absence of the polymorphism, are able to adapt their walking pattern over a period of trial and error practice, however the presence of the polymorphism influences the rate at which this is achieved.

The influence of high intensity exercise and the Val66Met polymorphism on circulating BDNF and locomotor learning

“…The temporal measure of limb phasing was calculated as previously reported (Helm et al, 2015; Tyrell et al, 2014, 2015). Briefly, a calculation of limb phase for each leg provides a measure of the difference in time between the contralateral limb’s peak flexion and the ipsilateral limb’s peak extension, normalized by the ipsilateral limb’s stride duration.…”

“…Splitting the treadmill belts in a 2: 1 or 3:1 ratio elicits an asymmetry in subject’s locomotor pattern and requires subjects to utilize trial and error practice to return to their baseline walking pattern. The rate and magnitude of reduction of this asymmetry within-session, as well as across sessions has previously been utilized to explore differences in locomotor learning in various populations (Helm et al, 2015; Morton & Bastian, 2006; Reisman et al, 2010; Tyrell et al, 2014). …”

“…A value of 0 therefore reflects a pattern identical to baseline (a)symmetry. In order to account for individual differences in the initial (a)symmetry at the start of split-belt walking, individual stride data was normalized by initial perturbation (Helm et al, 2015; Vasudevan et al, 2011). Normalization was achieved by dividing each symmetry value by the initial perturbation value, where initial perturbation was defined as the average of the first 3 strides during adaptation (Vasudevan et al, 2011).…”

“…In healthy humans, presence of the polymorphism has been associated with altered cortical activation and short term plasticity (Beste et al, 2010; Cheeran et al, 2008; McHughen et al, 2010) as well as altered skill acquisition and learning (Beste et al, 2010; Joundi et al, 2012; Kleim et al, 2006; McHughen et al, 2010). In addition, presence of the polymorphism has recently been shown to influence the rate of motor learning in individuals post-stroke (Helm, Tyrell, Pohlig, Brady, & Reisman, 2015). It is currently unknown whether presence of the Val66Met polymorphism would attenuate release of BDNF in response to exercise in humans and if this attenuation would impact motor learning.…”

Factors affecting post-stroke motor recovery: Implications on neurotherapy after brain injury

“…This polymorphism has been shown to partially affect activity-dependent BDNF secretion by reducing BDNF secretion by 30% in Met/Met neurons in-vitro [90] and to impair motor skill acquisition in-vivo [78,79]. In patients with ischemic stroke, the Val66Met allele was associated with poor outcomes and physical disability after stroke, and with slower motor recovery [83,91–93]. Analysis of pathophysiological difference between Val and Met patients suggests that both can retain the ability to recovery after stroke; however, the rate and trajectory of recovery appears to be difference [94].…”