Experimental Brain Research

, Volume 235, Issue 3, pp 841–850 | Cite as

BDNF and LTP-/LTD-like plasticity of the primary motor cortex in Gilles de la Tourette syndrome

  • L. Marsili
  • A. Suppa
  • F. Di Stasio
  • D. Belvisi
  • N. Upadhyay
  • I. Berardelli
  • M. Pasquini
  • S. Petrucci
  • M. Ginevrino
  • G. Fabbrini
  • F. Cardona
  • G. Defazio
  • A. Berardelli
Research Article
First Online:
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Accepted:

Abstract

Gilles de la Tourette syndrome (GTS) is characterized by motor and vocal tics and often associated with obsessive–compulsive disorder (OCD). Responses to intermittent/continuous theta-burst stimulation (iTBS/cTBS), which probe long-term potentiation (LTP)-/depression (LTD)-like plasticity in the primary motor cortex (M1), are reduced in GTS. ITBS-/cTBS-induced M1 plasticity can be affected by brain-derived neurotrophic factor (BDNF) polymorphism. We investigated whether the BDNF polymorphism influences iTBS-/cTBS-induced LTP-/LTD-like M1 plasticity in 50 GTS patients and in 50 age- and sex-matched healthy subjects. In GTS patients, motor and psychiatric (OCD) symptom severity was rated using the Yale Global Tic Severity Scale (YGTSS) and the Yale–Brown Obsessive–Compulsive Scale (Y-BOCS). We compared M1 iTBS-/cTBS-induced plasticity in healthy subjects and in patients with GTS. We also compared responses to TBS according to BDNF polymorphism (Val/Val vs Met carriers) in patients and controls. Fourteen healthy subjects and 13 GTS patients were Met carriers. When considering the whole group of controls, as expected, iTBS increased whereas cTBS decreased MEPs. Differently, iTBS/cTBS failed to induce LTP-/LTD-like plasticity in patients with GTS. When comparing responses to TBS according to BDNF polymorphism, in healthy subjects, Met carriers showed reduced MEP changes compared with Val/Val individuals. Conversely, in patients with GTS, responses to iTBS/cTBS were comparable in Val/Val individuals and Met carriers. YGTSS and Y-BOCS scores were comparable in Met carriers and in Val/Val subjects. We conclude that iTBS and cTBS failed to induce LTP-/LTD-like plasticity in patients with GTS, and this was not affected by BDNF genotype.

Keywords

Tourette syndrome Brain-derived neurotrophic factor Primary motor cortex Cortical plasticity Theta-burst stimulation 

Abbreviations

GTS

Gilles de la Tourette syndrome

OCD

Obsessive–compulsive disorder

M1

Primary motor cortex

TBS

Theta-burst stimulation

iTBS

Intermittent theta-burst stimulation

cTBS

Continuous theta-burst stimulation

PAS

Paired associative stimulation

LTP

Long-term potentiation

LTD

Long-term depression

MEP

Motor-evoked potential

HS

Healthy subjects

BDNF

Brain-derived neurotrophic factor

Val

Valine

Met

Methionine

DSM-V

Diagnostic and statistical manual of mental disorders, fifth edition

YGTSS

Yale Global Tic Severity Scale

Y-BOCS

Yale–Brown Obsessive–Compulsive Scale

FDI

First dorsal interosseous muscle

RMT

Resting motor threshold

AMT

Active motor threshold

EMG

Electromyographic

DNA

Deoxyribonucleic acid

SNP

Single nucleotide polymorphism

PCR

Polymerase chain reaction

ANOVA

Analysis of variance

QPS

Quadri-pulse stimulation

COMT

Catechol-O-methyltransferase

DRD2

Dopamine D2 receptor

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Notes

Funding

This study was supported by the USA National Tourette Syndrome Association (TSA Research Grant 2011–2012).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no potential conflicts of interest.

Human and animals rights

The present research involved human participants and not animals.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

References

  1. Antal A, Chaieb L, Moliadze V, Monte-Silva K, Poreisz C, Thirugnanasambandam N et al (2010) Brain-derived neurotrophic factor (BDNF) gene polymorphisms shape cortical plasticity in humans. Brain Stimul 3:230–237CrossRefPubMedGoogle Scholar
  2. Bocchio-Chiavetto L, Miniussi C, Zanardini R, Gazzoli A, Bignotti S, Specchia C et al (2008) 5-HTTLPR and BDNF Val66Met polymorphisms and response to rTMS treatment in drug resistant depression. Neurosci Lett 43:130–134CrossRefGoogle Scholar
  3. Brandt VC, Niessen E, Ganos C, Kahl U, Bäumer T, Münchau A (2014) Altered synaptic plasticity in Tourette’s syndrome and its relationship to motor skill learning. PLoS ONE 9:e98417. doi: 10.1371/journal.pone.0098417 CrossRefPubMedPubMedCentralGoogle Scholar
  4. Chang L, Wang Y, Ji H, Dai D, Xu X, Jiang D et al (2014) Elevation of peripheral BDNF promoter methylation links to the risk of Alzheimer’s disease. PLoS ONE 9:e110773. doi: 10.1371/journal.pone.0110773 CrossRefPubMedPubMedCentralGoogle Scholar
  5. Cheeran B, Talelli P, Mori F, Koch G, Suppa A, Edwards M et al (2008) A common polymorphism in the brain-derived neurotrophic factor gene (BDNF) modulates human cortical plasticity and the response to rTMS. J Physiol 586:5717–5725CrossRefPubMedPubMedCentralGoogle Scholar
  6. Chen ZY, Patel PD, Sant G, Meng CX, Teng KK, Hempstead BL et al (2004) Variant brain-derived neurotrophic factor (BDNF) (Met66) alters the intracellular trafficking and activity-dependent secretion of wild-type BDNF in neurosecretory cells and cortical neurons. J Neurosci 24:4401–4411CrossRefPubMedGoogle Scholar
  7. Cirillo J, Hughes J, Ridding M, Thomas PQ, Semmler JG (2012) Differential modulation of motor cortex excitability in BDNF Met allele carriers following experimentally induced and use-dependent plasticity. Eur J Neurosci 36:2640–2649CrossRefPubMedGoogle Scholar
  8. Egan MF, Kojima M, Callicott JH, Goldberg TE, Kolachana BS, Bertolino A et al (2003) The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell 24:257–269CrossRefGoogle Scholar
  9. Erickson KI, Kim JS, Suever BL, Voss MW, Francis BM, Kramer AF (2008) Genetic contributions to age-related decline in executive function: a 10-year longitudinal study of COMT and BDNF polymorphisms. Front Hum Neurosci. doi: 10.3389/neuro.09.011.2008 PubMedPubMedCentralGoogle Scholar
  10. Figurov A, Pozzo-Miller LD, Olafsson P, Wang T, Lu B (1996) Regulation of synaptic responses to high-frequency stimulation and LTP by neurotrophins in the hippocampus. Nature 81:706–709CrossRefGoogle Scholar
  11. Foltynie T, Cheeran B, Williams-Gray CH, Edwards MJ, Schneider SA, Weinberger D et al (2009) BDNF val66met influences time to onset of levodopa induced dyskinesia in Parkinson’s disease. J Neurol Neurosurg Psychiatry 80:141–144CrossRefPubMedGoogle Scholar
  12. Fritsch B, Reis J, Martinowich K, Schambra HM, Ji Y, Cohen LG et al (2010) Direct current stimulation promotes BDNF-dependent synaptic plasticity: potential implications for motor learning. Neuron 66:198–204CrossRefPubMedPubMedCentralGoogle Scholar
  13. Gómez-Garre P, Huertas-Fernández I, Cáceres-Redondo MT (2014) BDNF Val66Met polymorphism in primary adult-onset dystonia: a case-control study and meta-analysis. Mov Disord 29:1083–1086CrossRefPubMedGoogle Scholar
  14. Goodman WK, Price LH, Rasmussen SA, Mazure C, Delgado P, Heninger GR et al (1989) The Yale-Brown obsessive compulsive scale. II. Validity. Arch Gen Psychiatry 46:1012–1016CrossRefPubMedGoogle Scholar
  15. Gunther J, Tian Y, Stamova B, Lit L, Corbett B, Ander B et al (2012) Catecholamine-related gene expression in blood correlates with tic severity in Tourette syndrome. Psychiatry Res 30:593–601CrossRefGoogle Scholar
  16. Hall D, Dhilla A, Charalambous A, Gogos JA, Karayiorgou M (2003) Sequence variants of the brain-derived neurotrophic factor (BDNF) gene are strongly associated with obsessive compulsive disorder. Am J Hum Genet 73:370–376CrossRefPubMedPubMedCentralGoogle Scholar
  17. Hemmings SM, Kinnear CJ, Van der Merwe L, Lochner C, Corfield VA, Moolman-Smook JC et al (2008) Investigating the role of the brain-derived neurotrophic factor (BDNF) val66met variant in obsessive–compulsive disorder (OCD). World J Biol Psychiatry 9:126–134CrossRefPubMedGoogle Scholar
  18. Hemmings SM, Martin L, Klopper M, van der Merwe L, Aitken L, de Wit E et al (2012) BDNF Val66Met and DRD2 Taq1A polymorphisms interact to influence PTSD symptom severity: a preliminary investigation in a South African population. Prog Neuropsychopharmacol Biol Psychiatry 10:273–280Google Scholar
  19. Huang YZ, Edwards MJ, Rounis E, Bhatia KP, Rothwell JC (2005) Theta burst stimulation of the human motor cortex. Neuron 45:201–206CrossRefPubMedGoogle Scholar
  20. Huertas-Fernández I, Gómez-Garre P, Madruga-Garrido M, Bernal-Bernal I, Bonilla-Toribio M, Martín-Rodríguez JF et al (2015) GDNF gene is associated with Tourette syndrome in a family study. Mov Disord 30:1115–1120. doi: 10.1002/mds.26279 CrossRefPubMedPubMedCentralGoogle Scholar
  21. Hwang J, Kim Y-H, Yoon KJ, Uhm KE, Chang WH (2015) Different responses to facilitatory rTMS according to BDNF genotype. Clin Neurophysiol 126:1348–1353CrossRefPubMedGoogle Scholar
  22. Jankovic J (2001) Tourette’s syndrome. N Engl J Med 345:1184–1192CrossRefPubMedGoogle Scholar
  23. Joundi RA, Lopez-Alonso V, Lago A, Brittain JS, Fernandez-Del-Olmo M, Gomez-Garre P et al (2012) The effect of BDNF val66met polymorphism on visuomotor adaptation. Exp Brain Res 223:43–50CrossRefPubMedGoogle Scholar
  24. Jung P, Ziemann U (2009) Homeostatic and nonhomeostatic modulation of learning in human motor cortex. J Neurosci 29:5597–5694CrossRefPubMedGoogle Scholar
  25. Katerberg H, Lochner C, Cath DC, de Jonge P, Bochdanovits Z, Moolman-Smook JC et al (2009) The role of the brain-derived neurotrophic factor (BDNF) val66met variant in the phenotypic expression of obsessive–compulsive disorder (OCD). Am J Med Genet B Neuropsychiatr Genet 5:1050–1062CrossRefGoogle Scholar
  26. Klaffke S, König IR, Poustka F, Ziegler A, Hebebrand J, Bandmann O (2006) Brain-derived neurotrophic factor: a genetic risk factor for obsessive–compulsive disorder and Tourette syndrome? Mov Disord 21:881–883CrossRefPubMedGoogle Scholar
  27. Kleim JA, Chan S, Pringle E, Schallert K, Procaccio V, Jimenez R et al (2006) BDNF val66met polymorphism is associated with modified experience-dependent plasticity in human motor cortex. Nat Neurosci 9:735–737CrossRefPubMedGoogle Scholar
  28. Krstić J, Buzadžić I, Milanović SD, Ilić NV, Pajić S, Ilić TV (2014) Low-frequency repetitive transcranial magnetic stimulation in the right prefrontal cortex combined with partial sleep deprivation in treatment-resistant depression: a randomized sham-controlled trial. J ECT 30:325–331CrossRefPubMedGoogle Scholar
  29. Leckman JF, Riddle MA, Hardin MT, Ort SI, Swartz KL, Stevenson J et al (1989) The Yale Global Tic Severity Scale: initial testing of a clinician-rated scale of tic severity. J Am Acad Child Adolesc Psychiatry 28:566–573CrossRefPubMedGoogle Scholar
  30. Li Voti P, Conte A, Suppa A, Iezzi E, Bologna M, Aniello MS et al (2011) Correlation between cortical plasticity, motor learning and BDNF genotype in healthy subjects. Exp Brain Res 212:91–99CrossRefPubMedGoogle Scholar
  31. Liu S, Cui J, Niu Z, Yi M, Zhang X, Che F et al (2015) Do obsessive–compulsive disorder and Tourette syndrome share a common susceptibility gene? An association study of the BDNF Val66Met polymorphism in the Chinese Han population. World J Biol Psychiatry 14:1–8CrossRefGoogle Scholar
  32. Lu B (2003) BDNF and activity-dependent synaptic modulation. Learn Mem 10:86–98CrossRefPubMedGoogle Scholar
  33. Martinowich K, Lu B (2008) Interaction between BDNF and serotonin: role in mood disorders. Neuropsychopharmacology 33:73–83CrossRefPubMedGoogle Scholar
  34. Martín-Rodríguez JF, Ruiz-Rodríguez MA, Palomar FJ, Cáceres-Redondo MT, Vargas L, Porcacchia P et al (2015) Aberrant cortical associative plasticity associated with severe adult Tourette syndrome. Mov Disord 30:431–435CrossRefPubMedGoogle Scholar
  35. Mastroeni C, Bergmann TO, Rizzo V, Ritter C, Klein C, Pohlmann I et al (2013) Brain-derived neurotrophic factor a major player in stimulation-induced homeostatic metaplasticity of human motor cortex? PLoS ONE 8:e57957. doi: 10.1371/journal.pone.0057957 CrossRefPubMedPubMedCentralGoogle Scholar
  36. McHughen SA, Rodriguez PF, Kleim JA, Kleim ED, Marchal Crespo L, Procaccio V et al (2010) BDNF val66met polymorphism influences motor system function in the human brain. Cereb Cortex 20:1254–1262CrossRefPubMedGoogle Scholar
  37. Missitzi J, Gentner R, Geladas N, Politis P, Karandreas N, Classen J et al (2011) Plasticity in human motor cortex is in part genetically determined. J Physiol 589:297–306CrossRefPubMedGoogle Scholar
  38. Nagel IE, Chicherio C, Li SC, von Oertzen T, Sander T, Villringer A et al (2008) Human aging magnifies genetic effects on executive functioning and working memory. Front Hum Neurosci 2:1CrossRefPubMedPubMedCentralGoogle Scholar
  39. Nakamura K, Enomoto H, Hanajima R, Hamada M, Shimizu E, Kawamura Y et al (2011) Quadri-pulse stimulation (QPS) induced LTP/LTD was not affected by Val66Met polymorphism in the brain-derived neurotrophic factor (BDNF) gene. Neurosci Lett 487:264–267CrossRefPubMedGoogle Scholar
  40. Neves-Pereira M, Mundo E, Muglia P, King N, Macciardi F, Kennedy JL (2002) The brain-derived neurotrophic factor gene confers susceptibility to bipolar disorder: evidence from a family-based association study. Am J Hum Genet 71:651–655CrossRefPubMedPubMedCentralGoogle Scholar
  41. Pezawas L, Verchinski BA, Mattay VS, Callicott JH, Kolachana BS, Straub RE et al (2004) The brain-derived neurotrophic factor val66met polymorphism and variation in human cortical morphology. J Neurosci 10:10099–10102CrossRefGoogle Scholar
  42. Pivac N, Kim B, Nedić G, Joo YH, Kozarić-Kovacić D, Hong JP et al (2009) Ethnic differences in brain-derived neurotrophic factor Val66Met polymorphism in Croatian and Korean healthy participants. Croat Med J 50:43–48CrossRefPubMedPubMedCentralGoogle Scholar
  43. Rossini PM, Barker AT, Berardelli A, Caramia MD, Caruso G, Cracco RQ et al (1994) Non-invasive electrical and magnetic stimulation of the brain, spinal cord and roots: basic principles and procedures for routine clinical application. Report of an IFCN committee. Electroencephalogr Clin Neurophysiol 91:79–92CrossRefPubMedGoogle Scholar
  44. Shimizu E, Hashimoto K, Iyo M (2004) Ethnic difference of the BDNF 196G/A (val66met) polymorphism frequencies: the possibility to explain ethnic mental traits. Am J Med Genet B Neuropsychiatr Genet 1:122–133CrossRefGoogle Scholar
  45. Soliman F, Glatt CE, Bath KG, Levita L, Jones RM, Pattwell SS et al (2010) A genetic variant BDNF polymorphism alters extinction learning in both mouse and human. Science 12:863–866CrossRefGoogle Scholar
  46. Stefan K, Kunesch E, Cohen LG, Benecke R, Classen J (2000) Induction of plasticity in the human motor cortex by paired associative stimulation. Brain 123:572–584CrossRefPubMedGoogle Scholar
  47. Suppa A, Cheeran B (2014) Further insights into the effect of BDNF genotype on non-invasive brain stimulation. Clin Neurophysiol 126:1281–1283CrossRefPubMedGoogle Scholar
  48. Suppa A, Belvisi D, Bologna M, Marsili L, Berardelli I, Moretti G et al (2011) Abnormal cortical and brain stem plasticity in Gilles de la Tourette syndrome. Mov Disord 26:1703–1710CrossRefPubMedGoogle Scholar
  49. Suppa A, Marsili L, Di Stasio F, Berardelli I, Roselli V, Pasquini M et al (2014) Cortical and brainstem plasticity in Tourette syndrome and obsessive–compulsive disorder. Mov Disord 29:1523–1531. doi: 10.1002/mds.25960 CrossRefPubMedGoogle Scholar
  50. Suppa A, Huang YZ, Funke K, Ridding MC, Cheeran B, Di Lazzaro V et al (2016) Ten years of theta burst stimulation in humans: established knowledge, unknowns and prospects. Brain Stimul 9:323–335. doi: 10.1016/j.brs.2016.01.006 CrossRefPubMedGoogle Scholar
  51. Tükel R, Gürvit H, Ozata B, Oztürk N, Ertekin BA, Ertekin E et al (2012) Brain-derived neurotrophic factor gene Val66Met polymorphism and cognitive function in obsessive–compulsive disorder. Am J Med Genet B Neuropsychiatr Genet 159:850–858CrossRefGoogle Scholar
  52. Ward DD, Summers MJ, Saunders NL, Ritchie K, Summers JJ, Vickers JC (2015) The BDNF Val66Met polymorphism moderates the relationship between cognitive reserve and executive function. Transl Psychiatry 5:590. doi: 10.1038/tp.2015.82 CrossRefGoogle Scholar
  53. Witte AV, Kurten J, Jansen S, Schirmacher A, Brand E, Sommer J et al (2012) Interaction of BDNF and COMT polymorphisms on paired-associative stimulation-induced cortical plasticity. J Neurosci 2:4553–4561CrossRefGoogle Scholar
  54. Woo NH, Teng HK, Siao CJ, Chiaruttini C, Pang PT, Milner TA et al (2005) The yin and yang of neurotrophin action. Nat Neurosci 8:1069–1077CrossRefPubMedGoogle Scholar
  55. Wu SW, Gilbert DL (2012) Altered neurophysiologic response to intermittent theta burst stimulation in Tourette syndrome. Brain Stimul 5:315–319CrossRefPubMedGoogle Scholar
  56. Yuan A, Su L, Yu S, Li C, Yu T, Sun J (2015) Association between DRD2/ANKK1 TaqIA polymorphism and susceptibility with Tourette syndrome: a meta-analysis. PLoS ONE 10:e0131060. doi: 10.1371/journal.pone.0131060 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • L. Marsili
    • 1
  • A. Suppa
    • 1
    • 2
  • F. Di Stasio
    • 2
  • D. Belvisi
    • 2
  • N. Upadhyay
    • 1
  • I. Berardelli
    • 1
  • M. Pasquini
    • 1
  • S. Petrucci
    • 1
    • 3
  • M. Ginevrino
    • 3
    • 4
  • G. Fabbrini
    • 1
    • 2
  • F. Cardona
    • 5
  • G. Defazio
    • 6
  • A. Berardelli
    • 1
    • 2
  1. 1.Department of Neurology and Psychiatry“Sapienza” University of RomeRomeItaly
  2. 2.IRCCS Neuromed InstitutePozzilliItaly
  3. 3.Neurogenetics UnitIRCCS Santa Lucia FoundationRomeItaly
  4. 4.Department of Molecular MedicineUniversity of PaviaPaviaItaly
  5. 5.Department of Pediatrics and Child Neuropsychiatry“Sapienza” University of RomeRomeItaly
  6. 6.Department of Neurological and Psychiatric SciencesUniversity of BariBariItaly

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