A common polymorphism in the brain-derived neurotrophic factor gene (BDNF) modulates human cortical plasticity and the response to rTMS (original) (raw)
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Brain-derived neurotrophic factor (BDNF) gene polymorphisms shape cortical plasticity in humans
Brain Stimulation, 2010
Background The brain-derived neurotrophic factor (BDNF) gene is involved in mechanisms of synaptic plasticity in the adult brain. It has been demonstrated that BDNF also plays a significant role in shaping externally induced human brain plasticity. Plasticity induced in the human motor cortex by intermittent thetaburst stimulation (iTBS) was impaired in individuals expressing the Val66Met polymorphism. Methods To explore whether this polymorphism is also important for other neuroplasticity-inducing tools in humans with modes of action differing from that of iTBS, namely, transcranial direct current (tDCS) and random noise stimulation (tRNS), we retrospectively analyzed the data of 64 subjects studied in our laboratory with regard to BDNF genotype. Results Fifteen subjects with the Val66Met allele, 46 subjects with the Val66Val allele, and 3 Met66Met carriers were identified. The response of the Val66Met allele carriers to stimulation differed in two protocols compared with the response of Val66Val individuals. For iTBS (15 subjects, 5 heterozygotes), plasticity could be only induced in the Val66Val allele carriers. However, for facilitatory tDCS (24 subjects, 10 heterozygotes), as well as for inhibitory tDCS, (19 subjects, 8 heterozygotes), carriers of the Val66-Met allele displayed enhanced plasticity, whereas for transcranial random noise stimulation (29 subjects, 8 heterozygotes), the difference between groups was not so pronounced. Conclusions BDNF polymorphism has a definite impact on plasticity in humans, which might differ according to the mechanism of plasticity induction. This impact of BDNF on plasticity should be taken into account for This study was initiated and funded by an unrestricted grant awarded by the Rose Foundation (L.C./W.P.) and by the Bernstein Center for Computational Neuroscience Göttingen (V.M./W.P.) (BMBF 01GQ0782).
BDNF Gene Polymorphisms and Motor Cortical Plasticity in Healthy Humans: When Should We Consider It
Journal of Neuroscience and Rehabilitation, 2014
Background: The brain-derived neurotrophic factor (BDNF) gene is involved in mechanisms of synaptic plasticity in the brain and has been demonstrated to also play a role in influencing brain plasticity induced by transcranial magnetic and electrical stimulation. Objective and methods: This is an update of a previous study from our laboratory. We retrospectively analysed the data of 115 healthy subjects participating in 130 experimental sessions, measuring the amplitude of motor evoked potentials (MEPs) before and after transcranial stimulation of the primary motor cortex (M1). We explored whether BDNF polymorphism shapes the effects of excitatory theta burst stimulation (iTBS, n=23), anodal (n=32) and cathodal (n=19) transcranial direct current (tDCS), random noise (tRNS, n=33) and alternating current (tACS, n=13) stimulation. Results: Although a trend toward altered plasticity was observed in Val-66Met allele carriers to stimulation with regard to all protocols compared with the response of Val66Val individuals, no significant GENOTYPE x TIME interaction was found. Conclusions: The BDNF polymorphism is suggested to have an impact on transcranial stimulation-induced plasticity in humans, which differs according to the mechanism of plasticity induction. However, according to our data, we suggest that genotyping in general, in transcranial stimulation studies including small number of subjects and at least when the M1 is stimulated, is not necessary. Nevertheless, the impact of BDNF on plasticity inducing protocols might be taken into account for e.g. in cognitive studies, when the prefrontal cortex is stimulated.
Frontiers in aging neuroscience, 2015
The brain derived neurotrophic factor (BDNF) Val66Met polymorphism and stimulation duration are thought to play an important role in modulating motor cortex plasticity induced by non-invasive brain stimulation (NBS). In the present study we sought to determine whether these factors interact or exert independent effects in older adults. Fifty-four healthy older adults (mean age = 66.85 years) underwent two counterbalanced sessions of 1.5 mA anodal transcranial direct current stimulation (atDCS), applied over left M1 for either 10 or 20 min. Single pulse transcranial magnetic stimulation (TMS) was used to assess corticospinal excitability (CSE) before and every 5 min for 30 min following atDCS. On a group level, there was an interaction between stimulation duration and BDNF genotype, with Met carriers (n = 13) showing greater post-intervention potentiation of CSE compared to Val66Val homozygotes homozygotes (n = 37) following 20 min (p = 0.002) but not 10 min (p = 0.219) of stimulatio...
PLoS ONE, 2013
Repetitive transcranial magnetic stimulation (rTMS) of the human motor hand area (M1 HAND ) can induce lasting changes in corticospinal excitability as indexed by a change in amplitude of the motor-evoked potential. The plasticity-inducing effects of rTMS in M1 HAND show substantial inter-individual variability which has been partially attributed to the val 66 met polymorphism in the brain-derived neurotrophic factor (BDNF) gene. Here we used theta burst stimulation (TBS) to examine whether the BDNF val 66 met genotype can be used to predict the expression of TBS-induced homeostatic metaplasticity in human M1 HAND . TBS is a patterned rTMS protocol with intermittent TBS (iTBS) usually inducing a lasting increase and continuous TBS (cTBS) a lasting decrease in corticospinal excitability. In three separate sessions, healthy val 66 met (n = 12) and val 66 val (n = 17) carriers received neuronavigated cTBS followed by cTBS (n = 27), cTBS followed by iTBS (n = 29), and iTBS followed by iTBS (n = 28). Participants and examiner were blinded to the genotype at the time of examination. As expected, the first TBS intervention induced a decrease (cTBS) and increase (iTBS) in corticospinal excitability, respectively, at the same time priming the after effects caused by the second TBS intervention in a homeostatic fashion. Critically, val 66 met carriers and val 66 val carriers showed very similar response patterns to cTBS and iTBS regardless of the order of TBS interventions. Since none of the observed TBS effects was modulated by the BDNF val 66 met polymorphism, our results do not support the notion that the BDNF val 66 met genotype is a major player with regard to TBS-induced plasticity and metaplasticity in the human M1 HAND .
Correlation between cortical plasticity, motor learning and BDNF genotype in healthy subjects
Experimental Brain Research, 2011
There is good evidence that synaptic plasticity in human motor cortex is involved in behavioural motor learning; in addition, it is now possible to probe mechanisms of synaptic plasticity using a variety of transcranial brain-stimulation protocols. Interactions between these protocols suggest that they both utilise common mechanisms. The aim of the present experiments was to test how well responsiveness to brain-stimulation protocols and behavioural motor learning correlate with each other in a sample of 21 healthy volunteers. We also examined whether any of these measures were influenced by the presence of a Val66Met polymorphism in the BDNF gene since this is another factor that has been suggested to be able to predict response to tests of synaptic plasticity. In 3 different experimental sessions, volunteers underwent 5-Hz rTMS, intermittent theta-burst stimulation (iTBS) and a motor learning task. Blood samples were collected from each subject for BDNF genotyping. As expected, both 5-Hz rTMS and iTBS significantly facilitated MEPs. Similarly, as expected, kinematic variables of finger movement significantly improved during the motor learning task. Although there was a significant correlation between the effect of iTBS and 5-Hz rTMS, there was no relationship in each subject between the amount of TMS-induced plasticity and the increase in kinematic variables during motor learning. Val66Val and Val66Met carriers did not differ in their response to any of the protocols. The present results emphasise that although some TMS measures of cortical plasticity may correlate with each other, they may not always relate directly to measures of behavioural learning. Similarly, presence of the Val66Met BDNF polymorphism also does not reliably predict responsiveness in small groups of individuals. Individual success in behavioural learning is unlikely to be closely related to any single measure of synaptic plasticity.
Acta Neurologica Belgica, 2013
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.
neurogenetics, 2014
Val66Met (rs6265) is a gene variation, a single nucleotide polymorphism (SNP) in the brain-derived neurotrophic factor (BDNF) gene that codes for the protein BDNF. The substitution of Met for Val occurs at position 66 in the pro-region of the BDNF gene and is responsible for altered activity-dependent release and recruitment of BDNF in neurons. This is believed to manifest itself in an altered ability in neuroplasticity induction and an increased predisposition toward a number of neurological disorders. Many studies using neuroplasticity-inducing protocols have investigated the impact of the BDNF polymorphism on cortical modulation and plasticity; however, the results are partly contradictory and dependent on the paradigm used in a given study. The aim of this review is to summarize recent knowledge on the relationship of this BDNF SNP and neuroplasticity.
Brain-derived neurotrophic factor gene polymorphisms shape cortical plasticity in humans
Aktuelle Neurologie, 2009
Brain-derived neurotrophic factor (BDNF) is a candidate molecule for influencing the clinical response to antidepressant treatment. The aims of this study were to determine the relationship between the Val66Met polymorphism in the BDNF gene and the response to mirtazapine in 243 Korean subjects with major depressive disorder (MDD). The reduction in the Hamilton Depression score over the 8-week treatment period was not influenced by BDNF V66M genotypes. A marginal effect of genotype on somatic anxiety score was observed at baseline (P = 0.047 in the dominant model). However, genotype-time interaction had no effect on somatic anxiety score after the 8-week a treatment period. Plasma BDNF levels tended to increase during mirtazapine treatment, although without statistical significance (P = 0.055). After 8 weeks of mirtazapine treatment, plasma BDNF levels were higher in Met allele homozygotes (1499.7 ± 370.6 ng/mL) than in Val allele carriers (649.7 ± 158.5 ng/mL, P = 0.049). Our results do not support the hypothesis that the Val66Met promoter polymorphism in the BDNF gene influences the therapeutic response to mirtazapine in Korean MDD patients. However, our data indicate that this polymorphism results in increased plasma BDNF after mirtazapine treatment.
European Journal of Neuroscience, 2012
The purpose of this study was to investigate how healthy young subjects with one of three variants of the brain-derived neurotrophic factor (BDNF) gene modulate motor cortex excitability following experimentally induced and use-dependent plasticity interventions. Electromyographic recordings were obtained from the right first dorsal interosseous (FDI) muscle of 12 Val ⁄ Val, ten Val ⁄ Met and seven Met ⁄ Met genotypes (aged 18-39 years). Transcranial magnetic stimulation of the left hemisphere was used to assess changes in FDI motor-evoked potentials (MEPs) following three separate interventions involving paired associative stimulation, a simple ballistic task and complex visuomotor tracking task using the index finger. Val ⁄ Val subjects increased FDI MEPs following all interventions ( ‡ 25%, P < 0.01), whereas the Met allele carriers only showed increased MEPs after the simple motor task ( ‡ 26%, P < 0.01). In contrast to the simple motor task, there was no significant change in MEPs for the Val ⁄ Met subjects (7%, P = 0.50) and a reduction in MEPs for the Met ⁄ Met group ()38%, P < 0.01) following the complex motor task. Despite these differences in usedependent plasticity, the performance of both motor tasks was not different between BDNF genotypes. We conclude that modulation of motor cortex excitability is strongly influenced by the BDNF polymorphism, with the greatest differences observed for the complex motor task. We also found unique motor cortex plasticity in the rarest form of the BDNF polymorphism (Met ⁄ Met subjects), which may have implications for functional recovery after disease or injury to the nervous system in these individuals.