Skip to main content
Log in

Trace eyeblink conditioning in human subjects with cerebellar lesions

  • Research Article
  • Published:
Experimental Brain Research Aims and scope Submit manuscript

Abstract

Trace eyeblink conditioning was investigated in 31 patients with focal cerebellar lesions and 19 age-matched controls. Twelve patients presented with lesions including the territory of the superior cerebellar artery (SCA). In 19 patients lesions were restricted to the territory of the posterior inferior cerebellar artery (PICA). A 3D magnetic resonance imaging was used to determine the extent of the cortical lesion and possible involvement of cerebellar nuclei. Eyeblink conditioning was performed using a 40 ms tone as conditioned stimulus (CS) followed by a stimulus free trace-interval of 400 ms and a 100 ms air-puff as unconditioned stimulus (US). In SCA patients with lesions including parts of the cerebellar interposed nucleus trace eyeblink conditioning was significantly impaired. Pure cortical lesions of the superior cerebellum were not sufficient to reduce acquisition of trace conditioned eyeblink responses. PICA patients were not impaired in trace eyeblink conditioning. Consistent with animal studies the findings of the present human lesion study suggest that, in addition to forebrain areas, the interposed nucleus is of importance in trace eyeblink conditioning. Although cortical cerebellar areas appear less important in trace compared with delay eyeblink conditioning, the present data strengthen the view that cerebellar structures contribute to different forms of eyeblink conditioning paradigms.

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
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  • Amarenco P, Rosengart A, DeWitt LD, Pessin MS, Caplan LR (1993) Anterior inferior cerebellar artery territory infarcts. Mechanisms and clinical features. Arch Neurol 59:154–161

    Google Scholar 

  • Attwell PJ, Ivarsson M, Millar L, Yeo CH (2002) Cerebellar mechanisms in eyeblink conditioning. Ann NY Acad Sci 978:79–92

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Christian KM, Thompson RF (2003) Neural substrates of eyeblink conditioning: acquistion and retention. Learn Mem 11:427–455

    Article  Google Scholar 

  • Clark GA, McCormick DA, Lavond DG, Thompson RF (1984) Effects of lesions of cerebellar nuclei on conditioned behavioral and hippocampal neuronal responses. Brain Res 291:125–136

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Clark RE, Manns JR, Squire LR (2002) Classical conditioning, awareness, and brain systems. Trends Cogn Sci 6:524–531

    Article  PubMed  Google Scholar 

  • Daum I, Channon S, Canavan AG (1989) Classical conditioning in patients with severe memory problems. J Neurol Neurosurg Psychiatry 52:47–51

    Article  PubMed  CAS  Google Scholar 

  • Daum I, Schugens MM, Ackermann H, Lutzenberger W, Dichgans J, Birbaumer N (1993) Classical conditioning after cerebellar lesions in humans. Behav Neurosci 107:748–756

    Article  PubMed  CAS  Google Scholar 

  • Dimitrova A, Weber J, Redies C, Kindsvater K, Maschke M, Kolb FP, Forsting M, Diener HC, Timmann D (2002) MRI atlas of the human cerebellar nuclei. Neuroimage 17:240–255

    Article  PubMed  CAS  Google Scholar 

  • Evans AC, Kamber M, Collins DL, MacDonald D (1994) An MRI-based probablistic atlas of neuroanatomy. In: Shorvon S, Fish D, Andermann F, Bydder GM, Stefan H (eds) Magnetic resonance scanning and epilepsy, Plenum, NY, pp 263–274

  • Fortier CB, Disterhoft JF, McGlinchey-Berroth R (2000) Cerebellar cortical degeneration disrupts discrimination learning but not delay or trace classical eyeblink conditioning. Neuropsychology 14:537–550

    Article  PubMed  CAS  Google Scholar 

  • Gerwig M, Dimitrova A, Kolb FP, Maschke M, Brol B, Kunnel A, Böring D, Thilmann AF, Forsting M, Diener HC, Timmann D (2003) Comparison of eyeblink conditioning in patients with superior and posterior inferior cerebellar lesions. Brain 126:71–94

    Article  PubMed  CAS  Google Scholar 

  • Gerwig M, Dimitrova A, Maschke M, Kolb FP, Forsting M, Timmann D (2004) Amplitude changes of unconditioned eyeblink responses in patients with cerebellar lesions. Exp Brain Res 155:341–351

    Article  PubMed  CAS  Google Scholar 

  • Green JT, Woodruff-Pak DS (2000) Eyeblink classical conditioning: hippocampal formation is for neutral stimulus associations as cerebellum is for association-response. Psychol Bull 126:138–158

    Article  PubMed  CAS  Google Scholar 

  • Gruart A, Guillazo-Blanch G, Fernandez-Mas R, Jimenez-Diaz L, Delgado-Garcia JM (2000) Cerebellar posterior interpositus nucleus as an enhancer of classically conditioned eyelid responses in alert cats. J Neurophysiol 84:2680–2690

    PubMed  CAS  Google Scholar 

  • James GO, Hardiman MJ, Yeo CH (1987) Hippocampal lesions and trace conditioning in the rabbit. Behav Brain Res 23:109–116

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Kirsch P, Achenbach C, Kirsch M, Heinzmann M, Schienle A, Vaitl D (2003) Cerebellar and hippocampal activation during eyeblink conditioning depends on the experimental paradigm: a MEG study. Neural Plasticity 10:291–301

    Article  PubMed  Google Scholar 

  • Kishimoto Y, Kawahara S, Suzuki M, Mori H, Mishina M, Kirino Y (2001) Classical eyeblink conditioning in glutamate receptor subunit delta 2 mutant mice is impaired in the delay paradigm but not in the trace paradigm. Eur J Neurosci 13:1249–1253

    Article  PubMed  CAS  Google Scholar 

  • Kotani S, Kawahara S, Kirino Y (2003) Trace eyeblink conditioning in decerebrate guinea pigs. Eur J Neurosci 17:1445–1454

    Article  PubMed  Google Scholar 

  • Kronforst-Collins MA, Disterhoft JF (1998) Lesions of the caudal area of rabbit medial prefrontal cortex impair trace eyeblink conditioning. Neurobiol Learn Mem 69:147–162

    Article  PubMed  CAS  Google Scholar 

  • McEchron MD, Disterhoft JF (1997) Sequence of single neuron changes in CA1 hippocampus of rabbits during acquisition of trace eyeblink conditioned responses. J Neurophysiol 78:1030–1044

    PubMed  CAS  Google Scholar 

  • McGlinchey-Berroth R, Carrillo MC, Gabrieli JD, Brawn CM, Disterhoft JF (1997) Impaired trace eyeblink conditioning in bilateral, medial-temporal lobe amnesia. Behav Neurosci 111:873–882

    Article  PubMed  CAS  Google Scholar 

  • Middleton FA, Strick PL (1994) Anatomical evidence for cerebellar and basal ganglia involvement in higher cognitive function. Science 266:458–461

    Article  PubMed  CAS  Google Scholar 

  • Moyer JR Jr, Deyo RA, Disterhoft JF (1990) Hippocampectomy disrupts trace eye-blink conditioning in rabbits. Behav Neurosci 104:243–252

    Article  PubMed  Google Scholar 

  • Ongerboer de Visser BW (1983a) Anatomical and functional organization of reflexes involving the trigeminal system in man: jaw reflex, blink reflex, corneal reflex, and exteroceptive suppression. In: Desmedt JE (ed) Advances in Neurology, Raven Press, NY, pp 727–738

    Google Scholar 

  • Ongerboer de Visser BW (1983b) Comparative study of corneal and blink reflex latencies in patients with segmental or with cerbral lesions. In: Desmedt JE (ed) Advances in Neurology, Raven Press, NY, pp 757–772

    Google Scholar 

  • Peshori KR, Schicatano EJ, Gopalaswamy R, Sahay E, Evinger C (2001) Aging of the trigeminal blink system. Exp Brain Res 136:351–363

    Article  PubMed  CAS  Google Scholar 

  • Port RL, Romano AG, Steinmetz JE, Mikhail AA, Patterson MM (1986) Retention and acquisition of classical trace conditioned responses by rabbits with hippocampal lesions. Behav Neurosci 100:745–752

    Article  PubMed  CAS  Google Scholar 

  • Ramnani N, Toni I, Josephs O, Ashburner J, Passingham RE (2000) Learning- and expectation-related changes in the human brain during motor learning. J Neurophysiol 84:3026–3035

    PubMed  CAS  Google Scholar 

  • Rorden C, Brett M (2000) Stereotaxic display of brain lesions. Behav Neurol 12:191–200

    PubMed  Google Scholar 

  • Schmahmann JD, Dojon J, Toga AW, Petrides M, Evans AC (2000) MRI atlas of the human cerebellum. Academic Press, San Diego, CA

    Google Scholar 

  • Sears LL, Steinmetz JE (1990) Acquisition of classically conditioned-related activity in the hippocampus is affected by lesions of the cerebellar interpositus nucleus. Behav Neurosci 104:681–692

    Article  PubMed  CAS  Google Scholar 

  • Sears LL, Logue SF, Steinmetz JE (1996) Involvement of the ventrolateral thalamic nucleus in rabbit classical eyeblink conditioning. Behav Brain Res 74:105–117

    Article  PubMed  CAS  Google Scholar 

  • Solomon PR, Van der Schaaf ER, Thompson RF, Weisz DJ (1986) Hippocampus and trace conditioning of the rabbit’s classically conditioned nictitating membrane response. Behav Neurosci 100:729–744

    Article  PubMed  CAS  Google Scholar 

  • Steinmetz JE (2000) Brain substrates of classical eyeblink conditioning: a highly localized but also distributes system. Behav Brain Res 110:13–24

    Article  PubMed  CAS  Google Scholar 

  • Takehara K, Kawahara S, Takatsuki K, Kirino Y (2002) Time-limited role of the hippocampus in the memory for trace eyeblink conditioning in mice. Brain Res 951:183–190

    Article  PubMed  CAS  Google Scholar 

  • Takehara K, Kawahara S, Kirino Y (2003) Time-dependent reorganization of the brain components underlying memory retention in trace eyeblink conditioning. J Neurosci 23:9897–9905

    PubMed  CAS  Google Scholar 

  • Thompson RF, Bao S, Chen L, Cipriano BD, Grethe JS, Kim JJ, Thompson JK, Tracy JA, Weninger MS, Krupa DJ (1997) Associative learning. Int Rev Neurobiol 41:151–189

    PubMed  CAS  Google Scholar 

  • Thompson RF, Swain R, Clark R, Shinkman P (2000) Intracerebellar conditioning-Brogden and Gantt revisited. Behav Brain Res 110:3–11

    Article  PubMed  CAS  Google Scholar 

  • Timmann D, Gerwig M, Frings M, Maschke M, Kolb FP (2004) Eyeblink conditioning in patients with hereditary ataxia: a 1 year follow-up study. Exp Brain Res 162:332–345

    Article  Google Scholar 

  • Topka H, Valls-Sole J, Massaquoi SG, Hallett M (1993) Deficit in classical conditioning in patients with cerebellar degeneration. Brain 116:961–969

    Article  PubMed  Google Scholar 

  • Trouillas P, Takayanagi T, Hallett M, Currier RD, Subramony SH, Wessel K, Bryer A, Diener HC, Massaquoi S, Gomez CM, Coutinho P, Ben Hamida M, Campanella G, Filla A, Schut L, Timmann D, Honnorat J, Nighoghossian N, Manyam B (1997) 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 145:205–211

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Weible AP, McEchron MD, Disterhoft JF (2000) Cortical involvement in acquisition and extinction of trace eyeblink conditioning. Behav Neurosci 114:1058–1067

    Article  PubMed  CAS  Google Scholar 

  • Weiss C, Bouwmeester H, Power JM, Disterhoft JF (1999) Hippocampal lesions prevent trace eyeblink conditioning in the freely moving rat. Behav Brain Res 99:123–132

    Article  PubMed  CAS  Google Scholar 

  • Woodruff-Pak DS, Lavond DG, Thompson RF (1985) Trace conditioning: abolished by cerebellar nuclear lesions but not lateral cerebellar cortex aspirations. Brain Res 348:249–260

    Article  PubMed  CAS  Google Scholar 

  • Woodruff-Pak DS (1993) Eyeblink classical conditioning in H. M.: delay and trace paradigms. Behav Neurosci 107:911–925

    Article  PubMed  CAS  Google Scholar 

  • Woodruff-Pak DS, Papka M, Ivry RB (1996) Cerebellar involvement in eyeblink classical conditioning in humans. Neuropsychology 10:443–458

    Article  Google Scholar 

  • Woodruff-Pak DS, Levin SI, Chae M, Kim SE, Meisler MH (2004) Delay classical eyeblink conditioning and morris water maze are impaired in mice with conditional inactivation of SCN8A (Nav1.6) in cerebellar Purkinje cells. Program No. 325.16, Abstract Viewer/Itinerary Planner. Society for Neuroscience, Online, Washington, DC

  • Yamamoto T, Yoshida K, Yoshikawa H, Kishimoto Y, Oka H (1992) The medial dorsal nucleus is one of the thalamic relays of the cerebellocerebral responses to the frontal association cortex in the monkey: horseradish peroxidase and fluorescent dye double staining study. Brain Res 579:315–320

    Article  PubMed  CAS  Google Scholar 

  • Yeo CH, Hesslow G (1998) Cerebellum and conditioned reflexes. Trends Cogn Sci 2:322–330

    Article  Google Scholar 

Download references

Acknowledgments

The authors like to thank Beate Brol for help in eyeblink data analysis and preparation of the figures. The study was supported by a grant of the Deutsche Forschungsgemeinschaft (Ti 239/7-1).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to D. Timmann.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gerwig, M., Haerter, K., Hajjar, K. et al. Trace eyeblink conditioning in human subjects with cerebellar lesions. Exp Brain Res 170, 7–21 (2006). https://doi.org/10.1007/s00221-005-0171-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00221-005-0171-2

Keywords

Navigation