Skip to main content
Log in

Long Trace Eyeblink Conditioning Is Largely Preserved in Essential Tremor

  • Original Paper
  • Published:
The Cerebellum Aims and scope Submit manuscript

Abstract

The cerebellum and the prefrontal cortex are assumed to play a role in the pathophysiology of essential tremor (ET). Trace eyeblink conditioning with a long interstimulus interval relies on an intact function of the hippocampus, prefrontal cortex (PFC), and, although marginally, of the cerebellum. The aim of the present study was to evaluate whether long trace eyeblink conditioning is impaired in patients with ET. In 18 patients with ET and 18 controls, a long trace conditioning paradigm was applied. Following 100 paired conditioned response-unconditioned response trials, 30 conditioned response alone trials were given as extinction trials. The degree of tremor and the presence of accompanying cerebellar signs were determined based on clinical scales. The acquisition of conditioned eyeblink responses was not impaired in the group of all patients compared to controls (mean total incidences of conditioned responses in patients 23.3 ± 14.5%, in controls 24.1 ± 13.9%; P = 0.88). In the subgroup of six patients with cerebellar signs, incidences of conditioned responses were numerically but not significantly lower (16.4 ± 9.9%) compared to patients without cerebellar signs (26.8 ± 15.5%; P = 0.16). Trace eyeblink conditioning with a long interstimulus interval was not impaired in subjects with ET. Patients with clinical cerebellar signs presented slightly reduced conditioning. Areas of the PFC contributing to trace eyeblink conditioning appear less affected in ET. Future studies also using a shorter trace interval should include a larger group of subjects in all stages of ET.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Louis ED, Ferreira JJ. How common is the most common adult movement disorder? Update on the worldwide prevalence of essential tremor. Mov Disord. 2010;25(5):534–41.

    Article  Google Scholar 

  2. Boutin E, Vaugoyeau M, Eusebio A, Azulay JP, Witjas T. News and controversies regarding essential tremor. Rev Neurol. 2015;171:415–25.

    Article  CAS  Google Scholar 

  3. Deuschl G, Petersen I, Lorenz D, Christensen K. Tremor in the elderly: essential and aging-related tremor. Mov Disord. 2015;30:1327–34.

    Article  Google Scholar 

  4. Stolze H, Petersen G, Raethjen J, Wenzelburger R, Deuschl G. The gait disorder of advanced essential tremor. Brain. 2001;124:2278–86.

    Article  CAS  Google Scholar 

  5. Helmchen C, Hagenow A, Miesner J, Sprenger A, Rambold H, Wenzelburger R, et al. Eye movement abnormalities in essential tremor may indicate cerebellar dysfunction. Brain. 2003;126:1319–32.

    Article  CAS  Google Scholar 

  6. Louis ED, Lee M, Babij R, Ma K, Cortés E, Vonsattel JP, et al. Reduced Purkinje cell dendritic arborization and loss of dendritic spines in essential tremor. Brain. 2014;137:3142–8.

    Article  Google Scholar 

  7. Bagepally BS, Bhatt MD, Chandran V, Saini J, Bharath RD, Vasudev MK, et al. Decrease in cerebral and cerebellar gray matter in essential tremor: a voxel-based morphometric analysis under 3T MRI. J Neuroimaging. 2012;22:275–8.

    Article  Google Scholar 

  8. Benito-Leon J, Alvarez-Linera J, Hernandez-Tamames JA, Alonso-Navarro H, Jimenez-Jimenez FJ, Louis ED. Brain structural changes in essential tremor: voxel-based morphometry at 3-tesla. J Neurol Sci. 2009;287:138–42.

    Article  Google Scholar 

  9. Cerasa A, Messina D, Nicoletti G, Novellino F, Lanza P, Condino F, et al. Cerebellar atrophy in essential tremor using an automated segmentation method. AJNR. 2009;30:1240–3.

    Article  CAS  Google Scholar 

  10. Wang M, Yang Y, Wang CJ, Gamo NJ, Jin LE, Mazer JA, et al. NMDA receptors subserve persistent neuronal firing during working memory in dorsolateral prefrontal cortex. Neuron. 2013;77:736–49.

    Article  CAS  Google Scholar 

  11. Passamonti L, Novellino F, Cerasa A, Chiriaco C, Rocca F, Matina MS, et al. Altered cortical-cerebellar circuits during verbal working memory in essential tremor. Brain. 2011;134:2274–86.

    Article  Google Scholar 

  12. Moyer JR Jr, Deyo RA, Disterhoft JF. Hippocampectomy disrupts trace eye-blink conditioning in rabbits. Behav Neurosci. 1990;104:243–52.

    Article  Google Scholar 

  13. Solomon PR, Vander Schaaf ER, Thompson RF, Weisz DJ. Hippocampus and trace conditioning of the rabbit's classically conditioned nictitating membrane response. Behav Neurosci. 1986;100:729–44.

    Article  CAS  Google Scholar 

  14. Weiss C, Bouwmeester H, Power JM, Disterhoft JF. Hippocampal lesions prevent trace eyeblink conditioning in the freely moving rat. Behav Brain Res. 1999;99:123–32.

    Article  CAS  Google Scholar 

  15. Tseng W, Guan R, Disterhoft JF, Weiss C. Trace eyeblink conditioning is hippocampally dependent in mice. Hippocampus. 2004;14:58–65.

    Article  CAS  Google Scholar 

  16. Kronforst-Collins MA, Disterhoft JF. Lesions of the caudal area of rabbit medial prefrontal cortex impair trace eyeblink conditioning. Neurobiol Learn Mem. 1998;69:147–62.

    Article  CAS  Google Scholar 

  17. Weible AP, McEchron MD, Disterhoft JF. Cortical involvement in acquisition and extinction of trace eyeblink conditioning. Behav Neurosci. 2000;114:1058–67.

    Article  CAS  Google Scholar 

  18. McLaughlin J, Skaggs H, Churchwell J, Powell DA. Medial prefrontal cortex and pavlovian conditioning: trace versus delay conditioning. Behav Neurosci. 2002;37-47(16):116.

    Google Scholar 

  19. Powell DA, Churchwell J, Burriss L. Medial prefrontal lesions and pavlovian eyeblink and heart rate conditioning: effects of partial reinforcement on delay and trace conditioning in rabbits. Behav Neurosci. 2005;119:180–9.

    Article  CAS  Google Scholar 

  20. Chen H, Yang L, Xu Y, Wu GY, Yao J, Zhang J, et al. Prefrontal control of cerebellum-dependent associative motor learning. Cerebellum. 2014;13:64–78.

    Article  Google Scholar 

  21. Christian KM, Thompson RF. Neural substrates of eyeblink conditioning: acquisition and retention. Learn Mem. 2003;10:427–55.

    Article  Google Scholar 

  22. Woodruff-Pak DS, Lavond DG, Thompson RF. Trace conditioning: abolished by cerebellar nuclear lesions but not lateral cerebellar cortex aspirations. Brain Res. 1985;348(2):249–60.

    Article  CAS  Google Scholar 

  23. Gruart A, Schreurs BG, del Toro ED, Delgado-Garcia JM. Kinetic and frequency-domain properties of reflex and conditioned eyelid responses in the rabbit. J Neurophysiol. 2000;83:836–52.

    Article  CAS  Google Scholar 

  24. Green JT, Arenos JD. Hippocampal and cerebellar single-unit activity during delay and trace eyeblink conditioning in the rat. Neurobiol Learn Mem. 2007;87:269–84.

    Article  Google Scholar 

  25. Plakke B, Freeman JH, Poremba A. Metabolic mapping of the rat cerebellum during delay and trace eyeblink conditioning. Neurobiol Learn Mem. 2007;88:11–8.

    Article  CAS  Google Scholar 

  26. Gerwig M, Haerter K, Hajjar K. Trace eyeblink conditioning in human subjects with cerebellar lesions. Exp Brain Res. 2006;170:7–21.

    Article  CAS  Google Scholar 

  27. Gerwig M, Esser AC, Guberina H, Frings M, Kolb FP, Forsting M, et al. Trace eyeblink conditioning in patients with cerebellar degeneration: comparison of short and long trace intervals. Exp Brain Res. 2008;187:85–96.

    Article  CAS  Google Scholar 

  28. Caro-Martin CR, Leal-Campanario R, Sánchez-Campusano R, Delgado-García JM, Gruart A. A variable oscillator underlies the measurement of time intervals in the rostral medial prefrontal cortex during classical eyeblink conditioning in rabbits. J Neurosci. 2015;35(44):14809–21.

    Article  CAS  Google Scholar 

  29. Deuschl G, Bain P, Brin M. Consensus statement of the Movement Disorder Society on tremor. Ad Hoc Scientific Committee. Mov Disord. 1998;13(Suppl 3):2–23.

    PubMed  Google Scholar 

  30. Cartford MC, Allgeier CA, Bickford PC. The effects of beta-noradrenergic receptor blockade on acquisition of eyeblink conditioning in 3-month- old F344 rats. Neurobiol Learn Mem. 2002;78:246–57.

    Article  CAS  Google Scholar 

  31. Fahn S, Tolosa E, Concepcion M. Clinical rating scale for tremor. In: Jankovic J, Tolosa E, editors. Parkinson's disease and movement disorders. 2nd ed. Baltimore: Williams & Wilkins; 1993. p. 271–80.

    Google Scholar 

  32. Trouillas P, Takayanagi T, Hallett M, Currier RD, Subramony SH, Wessel K, et al. International Cooperative Ataxia Rating Scale for pharmacological assessment of the cerebellar syndrome. The Ataxia Neuropharmacology Committee of the World Federation of Neurology. J Neurol Sci. 1997;145:205–11.

    Article  CAS  Google Scholar 

  33. Kronenbuerger M, Gerwig M, Brol B, Block F, Timmann D. Eyeblink conditioning is impaired in subjects with essential tremor. Brain. 2007;130:1538–51.

    Article  Google Scholar 

  34. Kronenbuerger M, Konczak J, Ziegler W, Buderath P, Frank B, Coenen VA, et al. Balance and motor speech impairment in essential tremor. Cerebellum. 2009;8:389–98.

    Article  Google Scholar 

  35. Woodruff-Pak DS, Papka M, Ivry RB. Cerebellar involvement in eyeblink classical conditioning in humans. Neuropsychol. 1996;10:443–58.

    Article  Google Scholar 

  36. Bracha V, Zhao L, Irwin KB, Bloedel JR. The human cerebellum and associative learning: dissociation between the acquisition, retention and extinction of conditioned eyeblinks. Brain Res. 2000;860:87–94.

    Article  CAS  Google Scholar 

  37. Gerwig M, Kolb FP, Timmann D. The involvement in the human cerebellum in eyeblink conditioning. Cerebellum. 2007;6:38–57.

    Article  CAS  Google Scholar 

  38. Manns JR, Clark RE, Squire LR. Awareness predicts the magnitude of single-cue trace eyeblink conditioning. Hippocampus. 2000;10:181–6.

    Article  CAS  Google Scholar 

  39. Clark RE, Squire LR. Classical conditioning and brain systems: the role of awareness. Science. 1998;280:77–81.

    Article  CAS  Google Scholar 

  40. Hopfner F, Haubenberger D, Galpern WR, Gwinn K, Van't Veer A, White S. Knowledge gaps and research recommendations for essential tremor. Parkinsonism Relat Disord. 2016;33:27–35.

    Article  Google Scholar 

  41. Fernandez KM, Roemmich RT, Stegemöller EL, Amano S, Thompson A, Okun MS, et al. Gait initiation impairments in both essential tremor and Parkinson's disease. Gait Posture. 2013;38:956–61.

    Article  Google Scholar 

  42. Roemmich RT, Zeilman PR, Vaillancourt DE, Okun MS, Hass CJ. Gait variability magnitude but not structure is altered in essential tremor. J Biomech. 2013;46(15):2682–7.

    Article  Google Scholar 

  43. Sharifi S, Nederveen AJ, Booij J, van Rootselaar AF. Neuroimaging essentials in essential tremor: a systematic review. Neuroimage Clin. 2014;5:217–31.

    Article  Google Scholar 

  44. Axelrad JE, Louis ED, Honig LS, Flores I, Ross GW, Pahwa R, et al. Reduced Purkinje cell number in essential tremor: a postmortem study. Arch Neurol. 2008;65:101–7.

    Article  Google Scholar 

  45. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, et al. The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol. 2007;114:97–109.

    Article  Google Scholar 

  46. Louis ED, Faust PL, Vonsattel JP, Honig LS, Rajput A, Rajput A, et al. Torpedoes in Parkinson's disease, Alzheimer's disease, essential tremor, and control brains. Mov Disord. 2009;24:1600–5.

    Article  Google Scholar 

  47. Shill HA, De La Vega FJ, Samanta J, Stacy M. Motor learning in essential tremor. Mov Disord. 2009;24:926–8.

    Article  Google Scholar 

  48. Gruart A, Guillazo-Blanch G, Fernández-Mas R, Jiménez-Díaz L, Delgado-García JM. Cerebellar posterior interpositus nucleus as an enhancer of classically conditioned eyelid responses in alert cats. J Neurophysiol. 2000;84(5):2680–90.

    Article  CAS  Google Scholar 

  49. Wada N, Kishimoto Y, Watanabe D, Kano M, Hirano T, Funabiki K, et al. Conditioned eyeblink learning is formed and stored without cerebellar granule cell transmission. Proc Natl Acad Sci U S A. 2007;104:16690–5.

    Article  CAS  Google Scholar 

  50. Jiménez-Díaz L, Navarro-López Jde D, Gruart A, Delgado-García JM. Role of cerebellar interpositus nucleus in the genesis and control of reflex and conditioned eyelid responses. J Neurosci. 2004;24(41):9138–45.

    Article  Google Scholar 

  51. Woodruff-Pak DS, Disterhoft JF. Where is the trace in trace conditioning? Trends Neurosci. 2008;31:105–12.

    Article  CAS  Google Scholar 

  52. Chandran V, Pal PK. Essential tremor: beyond the motor features. Parkinsonism Relat Disord. 2012;18:407–13.

    Article  Google Scholar 

  53. Múnera A, Gruart A, Muñoz MD, Fernández-Mas R, Delgado-García JM. Hippocampal pyramidal cell activity encodes conditioned stimulus predictive value during classical conditioning in alert cats. J Neurophysiol. 2001;86(5):2571–82.

    Article  Google Scholar 

  54. Kim JJ, Clark RE, Thompson RF. Hippocampectomy impairs the memory of recently, but not remotely, acquired trace eyeblink conditioned responses. Behav Neurosci. 1995;109:195–203.

    Article  CAS  Google Scholar 

  55. Takehara K, Kawahara S, Kirino Y. Time-dependent reorganization of the brain components underlying memory retention in trace eyeblink conditioning. J Neurosci. 2003;23:9897–905.

    Article  CAS  Google Scholar 

  56. Weiss C, Disterhoft JF. Eyeblink conditioning, motor control, and the analysis of limbic-cerebellar interactions. Behav Brain Sci. 1996;19:479–81.

    Article  Google Scholar 

  57. Weiss C, Weible AP, Galvez R, Disterhoft JF. Forebrain-cerebellar interactions during learning. Cellscience. 2006;3:1–31.

    Google Scholar 

  58. Siegel JJ. Modification of persistent responses in medial prefrontal cortex during learning in trace eyeblink conditioning. J Neurophysiol. 2014;112(9):2123–37.

    Article  Google Scholar 

  59. Weiss C, Disterhoft JF. Exploring prefrontal cortical memory mechanisms with eyeblink conditioning. Behav Neurosci. 2011;125:318–26.

    Article  Google Scholar 

  60. Robleto K, Poulos AM, Thompson RF. Brain mechanisms of extinction of the classically conditioned eyeblink response. Learn Mem. 2004;11:517–24.

    Article  Google Scholar 

  61. Perrett SP, Mauk MD. Extinction of conditioned eyelid responses requires the anterior lobe of cerebellar cortex. J Neurosci. 1995;15:2074–80.

    Article  CAS  Google Scholar 

  62. Medina JF, Nores WL, Mauk MD. Inhibition of climbing fibers is a signal for the extinction of conditioned eyelid responses. Nature. 2002;416:330–3.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors like to thank Beate Brol for her help in conducting the experiments, in data analysis, and preparing the figures.

Funding

KS received speaker honoraria from Allergan.

SJO has received no funding sources.

MK has received no funding sources, regardless of relationship to the current research in the article.

DT received grants from the German Research Foundation, the German Heredoataxia Foundation and Mercur Research Center Ruhr and a honorium from Bayer AG.

MG received speaker honoraria and/or travel reimbursement from Novartis, Pfizer and Ipsen Pharma and research support from MSD.

Author information

Authors and Affiliations

Authors

Contributions

KS: Research project; Statistical Analysis; Manuscript Preparation.

SJO: Research project; Statistical Analysis; Manuscript Preparation.

MK: Research project; Manuscript Preparation.

DT: Research project; Statistical Analysis; Manuscript Preparation.

MG: Research project; Statistical Analysis; Manuscript Preparation.

Corresponding author

Correspondence to Marcus Gerwig.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Solbach, K., Oostdam, SJ., Kronenbuerger, M. et al. Long Trace Eyeblink Conditioning Is Largely Preserved in Essential Tremor. Cerebellum 18, 67–75 (2019). https://doi.org/10.1007/s12311-018-0956-z

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12311-018-0956-z

Keywords

Navigation