Motor training can induce profound physiological plasticity within primary motor cortex, including changes in corticospinal output and motor map topography. Using transcranial magnetic stimulation, we show that training-dependent increases in the amplitude of motor-evoked potentials and motor map reorganization are reduced in healthy subjects with a val66met polymorphism in the brain-derived neurotrophic factor gene (BDNF), as compared to subjects without the polymorphism. The results suggest that BDNF is involved in mediating experience-dependent plasticity of human motor cortex

Chan, Sheila

Cramer, Steven C

Jimenez, Richard

Kleim, Jeffrey A

Pringle, Erin

Procaccio, Vincent

Schallert, Kellan

eScholarship - University of California

UC IrvineUC Irvine Previously Published WorksTitleBDNF val66met polymorphism is associated with modified experience-dependent plasticity in human motor cortexPermalinkhttps://escholarship.org/uc/item/8wh674kqJournalNature Neuroscience, 9(6)ISSN1097-6256AuthorsKleim, Jeffrey AChan, SheilaPringle, Erinet al.Publication Date2006-06-01DOI10.1038/nn1699Copyright InformationThis work is made available under the terms of a Creative Commons Attribution License, availalbe at https://creativecommons.org/licenses/by/4.0/ Peer reviewedeScholarship.org Powered by the California Digital LibraryUniversity of CaliforniaBDNF val66met polymorphismis associated with modifiedexperience-dependent plasticityin human motor cortexJeffrey A Kleim1,2, Sheila Chan3, Erin Pringle1,2, Kellan Schallert3,Vincent Procaccio4,5, Richard Jimenez4 & Steven C Cramer3Motor training can induce profound physiological plasticitywithin primary motor cortex, including changes in corticospinaloutput and motor map topography. Using transcranial magneticstimulation, we show that training-dependent increases inthe amplitude of motor-evoked potentials and motor mapreorganization are reduced in healthy subjects with aval66met polymorphism in the brain-derived neurotrophicfactor gene (BDNF), as compared to subjects without thepolymorphism. The results suggest that BDNF is involvedin mediating experience-dependent plasticity of humanmotor cortex.Motor cortex physiology is highly sensitive to motor experience.Transcranial magnetic stimulation (TMS) experiments in humansubjects demonstrate that motor training can induce reorganizationof movement representations1 and enhance corticospinal output2.Parallel animal studies show similar changes in cortical function thatare mediated by synaptic plasticity within cortical circuitry in responseto various neural signals3. BDNF has been identified as one of the keyneural signals orchestrating synaptic plasticity4 and is elevated withinmotor cortex in response to motor training5. A single nucleotidepolymorphism producing a valine-to-methionine substitution atcodon 66 (val66met) in the human BDNF gene is associated withabnormal cortical morphology6, memory impairments7 and reducedmedial temporal lobe activity8. We hypothesized that the presence ofthe val66met polymorphism would be associated with abnormaltraining-induced motor cortex plasticity.We recruited 78 healthy, right-handed subjects between the ages of18 and 29 (mean age 22.7 ± 1.4 years; all subjects provided informedwritten consent and all procedures were approved by the University ofCalifornia Irvine Institutional Review Board). We obtained bloodsamples, and the subjects were genotyped for the BDNF val66metpolymorphism. We carried out polymerase chain reaction (PCR)amplification of a 274-bp fragment as described previously9. Weperformed mutation screening with denaturing high-performanceliquid chromatography (DHPLC) analysis on Transgenomics WAVEsystem (Transgenomics)10. All homozygote mutant DNA samplesdetected by dHPLC were confirmed by sequencing. From this pool,11 Val/Met and 6 Met/Met subjects were identified; all agreed toparticipate in the study. The first 9 Val/Val subjects that agreed toparticipate were also recruited (Table 1).Subjects were tested on three fine-motor tasks: maximum fingertapping rate, nine-hole pegboard and pinch-grip strength. On aseparate day, we used single-pulse TMS to generate measures ofcorticospinal output to the first dorsal interosseous (FDI) muscle ofthe right hand. A T1-weighted volumetric anatomical magnetic reso-nance image (MRI) scan was sighted to each subject’s head usingstereotactic software (BrainSight). Surface electromyograms (EMG)were recorded from the right FDI using cup electrodes in a belly-tendonmontage with gain ¼ 10,000 and bandpass filters ¼ 30 Hz and1,000 Hz. A Magstim 2002 magnetic stimulator (Magstim) and afigure-of-eight 70-mm stimulation coil were used to apply TMS tothe left precentral gyrus. Each stimulation site was guided by a 1-cm2grid superimposed onto a digital image of the cortical surface. Thecortical point with the lowest motor threshold (LMT) for FDI was firstidentified. LMTwas determined to the nearest 1% of stimulator outputand defined as the point with the lowest intensity required to produce amotor-evoked potential (MEP)Z 50 mV in at least six of ten pulses. Ateach LMT site, a recruitment curve was generated by delivering tenstimuli at each of four intensity levels (90%, 130%, 110% and 150% ofTable 1 Subject pool characteristics as a function of genotypeVal/Val Val/Met Met/MetAge in years 23.2 (1.2) 22.4 (0.9) 20.8 (0.8)Male 4 6 4Female 5 5 2Asian 2 5 3Caucasian 7 5 1Hispanic 0 1 2Handedness score 1.9 (0.1) 1.8 (0.1) 1.9 (0.1)Peg board in s 18.9 (1.0) 19.4 (1.0) 20.9 (0.9)Finger tapping in taps per 10 s 60.0 (4.6) 57.7 (2.6) 64.6 (1.1)Pinch grip in kg 21.0 (2.4) 22.8 (1.2) 24.8 (1.6)LMT as % device output 41.9 (2.2) 42.1 (2.0) 41.8 (2.7)Genotype frequencies observed in our cohort (Val/Val 0.63, Val/Met 0.29, Met/Met 0.08)were in Hardy-Weinberg equilibrium, given the mixed population from which they weresampled. Mean (± s.e.m.) time to complete the nine-hole peg board task, number offinger taps in 10 s and maximum pinch-grip strength. Mean score on Edinburgh scalereflects handedness: –2 ¼ left-handed, 0 ¼ ambidextrous and +2 ¼ right-handed. Mean(± s.e.m.) lowest motor threshold (LMT).Received 17 January; accepted 17 April; published online 7 May 2006; doi:10.1038/nn16991Brain Research Rehabilitation Center, Malcom Randall VA Hospital, 1601 SW Archer Road, Gainesville, Florida 32608, USA. 2Mcknight Brain Institute, Department ofNeuroscience, University of Florida, PO Box 100244, Gainesville, Florida 32610, USA. 3Departments of Neurology and Anatomy & Neurobiology, University of CaliforniaIrvine Medical Center, 101 The City Drive, Building 53, Room 203, Orange, California 92868, USA. 4Department of Pediatrics, University of California Irvine, 2034 HewittHall, Irvine, California 92697, USA. 5Center for Molecular and Mitochondrial Medicine and Genetics, University of California Irvine, 2034 Hewitt Hall, Irvine, California92697, USA. Correspondence should be addressed to J.A.K. (jkleim@ufl.edu).NATURE NEUROSCIENCE VOLUME 9 [ NUMBER 6 [ JUNE 2006 735BR I E F COMMUNICAT IONS©2006 Nature Publishing Group  http://www.nature.com/natureneuroscienceLMT) in pseudorandomized order. At each intensity, MEP amplitudeswere measured and averaged across the ten pulses. After generating thisrecruitment curve, we systematically applied stimulation (110% LMT)in 1-cm increments across the cortical grid and noted the number ofpositive responses (3 of 5 MEPs were Z 50 mV). This procedure wascontinued until each positive site was surrounded by negative sites.The number of positive sites was then used to determine the FDIrepresentation area. We also calculated thecenter of gravity (COG) and the normalizedmap volume of the FDI representation11.Immediately after baseline TMS measures,subjects performed 30 min of FDI exercise:each subject was asked to press the 1 and 3keys on a keyboard with the right index fingeras fast as possible for 15 s, followed by a 15 sbreak; this was repeated ten times, followed bya 3 min break. Next, subjects adducted theright index finger to press the pad of a pinch-grip gauge (Jamar) every 5 s, reaching at least5 kg of force, for 5 min; this was followed by a2 min break. Subjects then performed a sec-ond round of each task. We again used TMSto derive a second MEP amplitude recruit-ment curve, cortical representational area,normalizedmap volume and center of gravity,using the same LMT value and site as inthe mapping before the FDI exercise. The percentage change in MEPamplitude after training was calculated at 110%, 130% and 150% LMT.One-way analysis of variance showed no significant effect of geno-type on peg-board time (F2,23¼ 0.29; P¼ 0.750), tapping rate (F2,23¼2.16; P ¼ 0.120) or pinch-grip strength (F2,23 ¼ 0.720; P ¼ 0.498;Table 1). We also found no significant effect of genotype on LMT(F2,23 ¼ 0.003; P ¼ 0.996; Table 1); similarly, there was no significanteffect of genotype (F1,23 ¼ 2.23; P ¼ 0.130) or genotype  intensity(F6,42¼ 0.60; P¼ 0.605) on baselineMEP amplitudes (SupplementaryTable 1 online). A repeated-measures analysis of variance revealed asignificant effect of the genotype  training interaction on FDI maparea (F2,23 ¼ 4.49; P ¼ 0.022). Val/Val subjects showed a significantincrease in mean FDI map area after training that was not observed inVal/Met andMet/Met subjects (Fig. 1a,b). We found a significant maineffect of genotype on percentage change in MEP amplitude at 110%(F2,23 ¼ 13.19; P ¼ 0.0002), 130% (F2,23 ¼ 5.39; P ¼ 0.012) and 150%LMT (F2,23 ¼ 5.50; P ¼ 0.011): Val/Val subjects showed a significantlygreater mean percentage increase in post-training MEP amplitude thanVal/Met and Met/Met subjects at all three stimulation levels (Fig. 2a).Further, we found a significant effect of the genotype  traininginteraction on normalized map volume (F2,23 ¼ 6.95; P ¼ 0.004):Val/Val subjects showed a significant post-training increase in meanmap volume that was not observed in Val/Met or Met/Met subjects(Fig. 2b). Finally, we found a significant effect of genotype(F2,23 ¼ 4.63; P ¼ 0.020) on the net shift in the center of gravity:Val/Val subjects showed a significantly greater mean shift in center ofgravity after training than Val/Met and Met/Met subjects (Fig. 2c).Although we observed no baseline differences in corticospinal out-put or motor map area between Val and Met subjects, a brief period ofmotor training enhanced corticospinal output and increased motormap area in Val/Val but not Val/Met or Met/Met subjects; the Val/Metand Met/Met subjects actually showed some training effects in theopposite direction. Thus, the physiological consequences of this BDNFpolymorphism may not manifest in the basal state but only becomeevident in response to behaviorally driven increases in neural activity.This is consistent with in vitro studies showing that transfection ofneurons with the BDNF met allele does not affect constitutive BDNFsecretion but does reduce BDNF secretion in response to neuronalstimulation7. This is also concordant with the observation that in micelacking the Bdnf gene, baseline synaptic physiology is normal but long-term potentiation of synaptic responses after neuronal stimulation isimpaired12. Further, in the current cohort, the presence of even a single15129Cortical area (cm2 )630Val/Val Val/MetGenotypeFDI map areaPre-trainingPost-trainingBDNF genotype and effects of training on map areaMet/MetVal/Val Val/MetGenotypeMet/MetPre-trainingPost-training*abFigure 1 Changes in motor map area with training. (a) Mean (± s.e.m.) FDIrepresentation area (*P o 0.05, Fisher’s protected test). (b) Representativemotor maps of FDI muscle representations from Val/Val, Val/Met and Met/Metsubjects superimposed onto a composite MRI image of the cortex. Blue dot,location of the LMT site. Green, positive sites. Red, negative sites.200 8.0 2.52.01.5Distance (cm)1.00.5Val/Val Val/MetGenotypeMet/Met7.06.05.04.0Units3.02.01.0Post-training MEP Map volume COG shiftVal/Val ***Val/Val Val/Met Met/MetVal/MetMet/Met150100 * ** * **500110%Percentage lowest motor threshold GenotypePercentage pre-training MEP130% 150%a b cFigure 2 Changes in MEP amplitude, map volume and center of gravity with training. (a) Mean(± s.e.m.) percentage of pretraining MEP amplitudes observed after training (that is, (MEPpost/MEPpre) 100) at 110%, 130% and 150% of lowest motor threshold (LMT). Changes in subthreshold MEPs (90%LMT) were not included owing to the inability to reliably evoke measurable MEPs. (b) Mean (± s.e.m.)normalized map volume. (c) Mean (± s.e.m.) center of gravity (COG) shift (*P o 0.05, Fisher’s protectedtest). There was no significant effect of the sex  genotype  intensity interaction on the change in MEPamplitude (F6,36 ¼ 0.74; P ¼ 0.45), on map volume (F2,20 ¼ 0.121; P ¼ 0.32) or on the change inCOG (F2,20 ¼ 0.05; P ¼ 0.94).736 VOLUME 9 [ NUMBER 6 [ JUNE 2006 NATURE NEUROSCIENCEBR I E F COMMUNICAT IONS©2006 Nature Publishing Group  http://www.nature.com/natureneurosciencemet allele was sufficient to modify changes in corticospinal output andmap organization. This is consistent with the finding that introductionof a single met allele interferes with BDNF secretion in vitro7.Notably, there were no differences between the different genotypeson the three fine-motor tasks used in this experiment. Detectingdifferences in motor performance might require more detailed motortesting to includemeasures of new, skilledmovement. Indeed, cognitivedifferences observed in subjects with the polymorphism are notgeneralized, being undetectable onmany cognitive tests8,13. The presentresults do, however, demonstrate that a single-nucleotide missensepolymorphism in the BDNF gene is associated with modified experi-ence-dependent plasticity in corticospinal output. These findings mayhave clinical implications, given the central role of BDNF to CNS repairafter injury14.Note: Supplementary information is available on the Nature Neuroscience website.ACKNOWLEDGMENTSWe thank S. Wolf, E. Orr, D. Ro and V. Le. Studies were carried out in theGeneral Clinical Research Center, College of Medicine, University of CaliforniaIrvine, with funds provided by the National Center for Research Resources(5M01RR 00827-29, NS-45563) and the US Public Health Service. Work wasconducted while J.A.K. was on a leave of absence from the Canadian Centrefor Behavioural Neuroscience at the University of Lethbridge.COMPETING INTERESTS STATEMENTThe authors declare that they have no competing financial interests.Published online at http://www.nature.com/natureneuroscienceReprints and permissions information is available online at http://npg.nature.com/reprintsandpermissions/1. Classen, J. et al. J. Neurophysiol. 79, 1117–1123 (1998).2. Pascual-Leone, A. J. Neurophysiol. 74, 1037–1045 (1995).3. Monfils, M.H., Plautz, E.J. & Kleim, J.A. Neuroscientist 11, 471–483 (2005).4. Lu, B. Learn. Mem. 10, 86–98 (2003).5. Klintsova, A.Y., Dickson, E., Yoshida, R. & Greenough, W.T. Brain Res. 1028, 92–104(2004).6. Pezawas, L. et al. J. Neurosci. 24, 10099–10102 (2004).7. Egan, M.F. et al. Cell. 112, 257–269 (2003).8. Hariri, A.R. et al. J. Neurosci. 23, 6690–6694 (2003).9. Sen, S. et al. Neuropsychopharmacology 28, 397–401 (2003).10.Oefner, P.J. & Underhill, P.A. in Current Protocols in Human Genetics (eds. Dracopoli,N.C. et al.) 7.10.1–7.10.12 (John Wiley and Sons, New York, 1998).11.Wolf, S.L. et al. Clin. Neurophysiol. 115, 1740–1747 (2004).12. Zakharenko, S.S. et al. Neuron 39, 975–990 (2003).13.Dempster, E. et al. Am. J. Med. Genet. B Neuropsychiatr. Genet. 134, 73–75(2005).14.Kleim, J.A., Jones, T.A. & Schallert, T. Neurochem. Res. 28, 1757–1769 (2003).NATURE NEUROSCIENCE VOLUME 9 [ NUMBER 6 [ JUNE 2006 737BR I E F COMMUNICAT IONS©2006 Nature Publishing Group  http://www.nature.com/natureneuroscience

English

BDNF val66met polymorphism is associated with modified experience-dependent plasticity in human motor cortex

https://escholarship.org/uc/item/8wh674kq

BDNF val66met polymorphism is associated with modified experience-dependent plasticity in human motor cortex.

Abstract

Similar works

Full text

Available Versions

eScholarship - University of California