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

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.

[1]  J. Rothwell,et al.  Homeostatic-like plasticity of the primary motor hand area is impaired in focal hand dystonia. , 2005, Brain : a journal of neurology.

[2]  Paul Greengard,et al.  Loss of bidirectional striatal synaptic plasticity in L-DOPA–induced dyskinesia , 2003, Nature Neuroscience.

[3]  J. Rothwell,et al.  Preconditioning of Low-Frequency Repetitive Transcranial Magnetic Stimulation with Transcranial Direct Current Stimulation: Evidence for Homeostatic Plasticity in the Human Motor Cortex , 2004, The Journal of Neuroscience.

[4]  Bai Lu,et al.  Activation of p75NTR by proBDNF facilitates hippocampal long-term depression , 2005, Nature Neuroscience.

[5]  Bai Lu,et al.  BDNF and activity-dependent synaptic modulation. , 2003, Learning & memory.

[6]  H. Siebner,et al.  Abnormal associative plasticity of the human motor cortex in writer's cramp. , 2003, Brain : a journal of neurology.

[7]  M. Nitsche,et al.  Pharmacological approach to the mechanisms of transcranial DC-stimulation-induced after-effects of human motor cortex excitability. , 2002, Brain : a journal of neurology.

[8]  John C Rothwell,et al.  Effect of physiological activity on an NMDA-dependent form of cortical plasticity in human. , 2008, Cerebral cortex.

[9]  Pablo Mir,et al.  Abnormalities in motor cortical plasticity differentiate manifesting and nonmanifesting DYT1 carriers , 2006, Movement disorders : official journal of the Movement Disorder Society.

[10]  Petti T. Pang,et al.  The yin and yang of neurotrophin action , 2005, Nature Reviews Neuroscience.

[11]  J. Rothwell,et al.  Theta Burst Stimulation of the Human Motor Cortex , 2005, Neuron.

[12]  L. Cohen,et al.  Induction of plasticity in the human motor cortex by paired associative stimulation. , 2000, Brain : a journal of neurology.

[13]  A Berardelli,et al.  Ovarian hormones and cortical excitability. An rTMS study in humans , 2004, Clinical Neurophysiology.

[14]  A. Quartarone,et al.  Rapid‐rate paired associative stimulation of the median nerve and motor cortex can produce long‐lasting changes in motor cortical excitability in humans , 2006, The Journal of physiology.

[15]  S. Cramer,et al.  BDNF val66met polymorphism is associated with modified experience-dependent plasticity in human motor cortex , 2006, Nature Neuroscience.

[16]  M. Egan,et al.  The BDNF val66met Polymorphism Affects Activity-Dependent Secretion of BDNF and Human Memory and Hippocampal Function , 2003, Cell.

[17]  Daniel Zeller,et al.  Depression of human corticospinal excitability induced by magnetic theta-burst stimulation: evidence of rapid polarity-reversing metaplasticity. , 2008, Cerebral cortex.

[18]  A. Meyer-Lindenberg,et al.  The Brain-derived Neurotrophic Factor Val66met Polymorphism and Variation in Human Cortical Morphology , 2022 .

[19]  N Birbaumer,et al.  Reorganization of Motor and Somatosensory Cortex in Upper Extremity Amputees with Phantom Limb Pain , 2001, The Journal of Neuroscience.

[20]  Michael A Nordstrom,et al.  Cortisol Inhibits Neuroplasticity Induction in Human Motor Cortex , 2008, The Journal of Neuroscience.

[21]  Richard S. J. Frackowiak,et al.  How does transcranial DC stimulation of the primary motor cortex alter regional neuronal activity in the human brain? , 2005, The European journal of neuroscience.

[22]  J. Rothwell,et al.  Consensus: Motor cortex plasticity protocols , 2008, Brain Stimulation.

[23]  Spartaco Santi,et al.  Induction of long-term potentiation and depression is reflected by corresponding changes in secretion of endogenous brain-derived neurotrophic factor. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[24]  B. Lu,et al.  Regulation of synaptic responses to high-frequency stimulation and LTP by neurotrophins in the hippocampus , 1996, Nature.

[25]  G. Linazasoro.  New ideas on the origin of L-dopa-induced dyskinesias: age, genes and neural plasticity. , 2005, Trends in pharmacological sciences.

[26]  Ulf Ziemann,et al.  Interindividual variability and age-dependency of motor cortical plasticity induced by paired associative stimulation , 2008, Experimental Brain Research.

[27]  M. Egan,et al.  Brain-Derived Neurotrophic Factor val66met Polymorphism Affects Human Memory-Related Hippocampal Activity and Predicts Memory Performance , 2003, The Journal of Neuroscience.