Elsevier

Behavioural Brain Research

Volume 212, Issue 2, 15 October 2010, Pages 143-151
Behavioural Brain Research

Research report
Evaluation of multiple-session delay eyeblink conditioning comparing patients with focal cerebellar lesions and cerebellar degeneration

https://doi.org/10.1016/j.bbr.2010.04.007Get rights and content

Abstract

The acquisition and timing of delay-conditioned eyeblink responses (CRs) have been shown to be significantly impaired in patients with disorders restricted to the cortex of the superior cerebellum. We were interested if patients improve incidences and timing of CRs across three sessions on three consecutive days.

A standard delay paradigm was used in 9 patients with diffuse cerebellar degeneration, 13 patients with ischemic cortical cerebellar lesions and in 13 controls. High-resolution magnetic resonance imaging (MR imaging) was used to ensure that hemispheral lobules VI and/ or Crus I were lesioned in all stroke patients with the interposed nuclei being preserved. On day 1 patients with stroke but not with degenerative disorders showed significant CR acquisition, although total CR incidences remained significantly lower than in controls. No further improvement was visible on days 2 and 3 neither in patients with focal lesions nor in patients with cerebellar degeneration. CRs occurred earlier in cerebellar patients, most pronounced in patients with degenerative disorders. In patients with stroke but not in the degenerative group timing had improved on the third day close to values of the control subjects.

Findings show that lesions of the cerebellar cortex produce permanent deficits in the acquisition of delay-conditioned eyeblink responses. Overall, mean CR incidence was higher in focal compared to degenerative disorders, most likely because the critical lobules (VI and Crus I) were lesioned only in part. Intact anterior lobe, which it thought to contribute to CR timing, may explain recovery of disordered timing in focal cerebellar patients.

Introduction

Extensive research in animals has shown that the cerebellum plays a key role in the acquisition, timing and retention of classical conditioned eyeblink responses (CRs), for review see [13], [29], [44], [50], [51]. Although there is general agreement that both the cerebellar cortex and nuclei contribute to delay eyeblink conditioning, there is ongoing discussion about their relative roles in this form of associative learning [10], [54]. For example, some authors report that the cerebellar cortex is essential for timing, but not for acquisition of CRs [41], [43]. Others, however, have shown that lesions of the critical areas of the cerebellar cortex are followed by a permanent inability to acquire CRs [3], [11], [52], [53].

Both cerebellar human lesion and functional brain imaging data show that the cerebellar cortex is involved in acquisition of the CR [9], [12], [17], [37], [48], [49]. Similar to animal studies, lobules VI and Crus I of the superior cerebellar hemisphere have been found to be of particular importance [17], [37], [53]. Beyond CR acquisition, appropriate timing of learned responses has been disrupted following lesions of the anterior cerebellar lobe [19].

Based on the human cerebellar lesion literature, however, it cannot be decided if lesions restricted to the cerebellar cortex are followed by a temporary or permanent learning deficit. Firstly, in the large majority of human cerebellar lesion studies only one conditioning session has been performed, including up to 100 paired CS-US trials [12], [17], [48], [49]. Secondly, many studies included patients with lesions of the cerebellar cortex and patients with additional lesions of the cerebellar nuclei. Animal studies show that the interposed nuclei are essential in delay eyeblink conditioning [34], [42], [43]. To better understand the function of the cerebellar cortex, patients with additional lesions of the interposed nuclei need to be excluded.

To date, sequential sessions have been applied in three studies [5], [31], [46]. These studies found no significant improvement of CR acquisition across testing sessions. The number of patients, however, was small in two of the studies (n = 1 [31]; n = 4 [5]). Furthermore, lesions included the cerebellar cortex and nuclei in some of the patients. In the third study, a larger group of patients with degeneration of the cerebellar cortex was examined. However, the time interval was long between sessions (6 months [46]).

The aim of the present study was to investigate a larger group of patients with lesions restricted to the cerebellar cortex in multiple conditioning sessions. One group of patients suffered from cerebellar degeneration, which is known to affect primarily the cerebellar cortex [33]. A second group included patients with focal cerebellar lesions. High-resolution magnetic resonance scans were used to acertain that lesions involved the critical lobules VI and/ or Crus I. Furthermore, patients with additional lesions of the interposed nuclei were excluded.

We asked the question whether patients with lesions restricted to the cerebellar cortex were able to improve CR acquisition across multiple testing sessions or not. In addition, possible changes of CR timing were assessed.

Section snippets

Subjects

A total of 27 cerebellar patients, 18 with focal ischemic lesions, nine with degenerative cerebellar disorders and 13 age- and sex-matched control subjects (7 male, 6 female; mean age 52.8 ± 15.0 years, range 22–66 years) were investigated. Informed consent was obtained from all subjects and the study was approved by the local Ethics Committee of the University of Duisburg-Essen. In patients with focal lesions MR imaging was used to ensure that cortical areas known as relevant in eyeblink

Volumetric measurements

Patients with degenerative disorders showed cerebellar atrophy to various degrees with the brainstem and cerebrum showing no effect. No abnormalities were observed in the control subjects. Fig. 1 shows volumes in cerebellar patients and controls expressed as %TICV. In addition, cerebellar volumes are visualized as percentage of volumes in controls. The normalized volume of the cerebrum was not different between groups (p = 0.31, unpaired t-test; Fig. 1A). In degenerative cerebellar patients the

Discussion

The present findings suggest that lesions of the cerebellar cortex are followed by permanent deficits in the acquisition and timing of delay-conditioned eyeblink responses in humans. Neither degenerative nor focal cerebellar patients showed a significant increase of CRs across training sessions. Patients with focal cerebellar lesions, however, were able to acquire some conditioned responses on day 1, most likely because lesions of the critical cortical areas (lobules VI and Crus I) were

Acknowledgements

This study was supported by a grant from the Bernd Fink-Foundation and the Deutsche Heredoataxie-Gesellschaft (DHAG). The authors like to thank Beate Brol for her help in conducting the experiments, in data analysis and preparing the figures.

References (54)

  • D.G. Lavond et al.

    Acquisition of classical conditioning without cerebellar cortex

    Behav Brain Res

    (1989)
  • N. Makris et al.

    MRI-based surface-assisted parcellation of human cerebellar cortex: an anatomically specified method with estimate of reliability

    Neuroimage

    (2005)
  • J.E. Steinmetz

    Brain substrates of classical eyeblink conditioning: a highly localized but also distributed system

    Behav Brain Res

    (2000)
  • R.F. Thompson et al.

    Associative learning

    Int Rev Neurobiol

    (1997)
  • R.F. Thompson et al.

    The role of the cerebellum in classical conditioning of discrete behavioral responses

    Neuroscience

    (2009)
  • D. Timmann et al.

    Current advances in lesion-symptom mapping of the human cerebellum

    Neuroscience

    (2009)
  • C. Yeo et al.

    Discrete lesion of the cerebellar cortex abolish the classically conditioned nictitating membrane response of the rabbit

    Behav Brain Res

    (1984)
  • C.H. Yeo et al.

    Cerebellum and conditioned reflexes

    Trends Cogn Sci

    (1998)
  • D. Aksenov et al.

    GABA neurotransmission in the cerebellar interposed nuclei: involvement in classically conditioned eyeblinks and neuronal activity

    J Neurophysiol

    (2004)
  • P.J. Attwell et al.

    Acquisition of eyeblink conditioning is critically dependent on normal function in cerebellar cortical lobule HVI

    J Neurosci

    (2001)
  • P.J. Attwell et al.

    Cerebellar mechanisms in eyeblink conditioning

    Ann N Y Acad Sci

    (2002)
  • V. Bracha et al.

    Patients with cerebellar lesions cannot acquire but are able to retain conditioned eyeblink reflexes

    Brain

    (1997)
  • D.T. Cheng et al.

    Neural substrates underlying human delay and trace eyeblink conditioning

    Proc Natl Acad Sci USA

    (2008)
  • K.M. Christian et al.

    Neural substrates of eyeblink conditioning: acquisition and retention

    Learn Mem

    (2003)
  • S.F. Cooke et al.

    Temporal properties of cerebellar-dependent memory consolidation

    J Neurosci

    (2004)
  • I. Daum et al.

    Classical conditioning after cerebellar lesions in humans

    Behav Neurosci

    (1993)
  • M. Gerwig et al.

    Comparison of eyeblink conditioning in patients with superior and posterior inferior cerebellar lesions

    Brain

    (2003)
  • Cited by (37)

    • Inactivation of the interpositus nucleus blocks the acquisition of conditioned responses and timing changes in conditioning-specific reflex modification of the rabbit eyeblink response

      2018, Neurobiology of Learning and Memory
      Citation Excerpt :

      The finding that inactivation of the IP blocked the development of CRs during delay eyeblink conditioning is in agreement with many electrolytic/excitotoxic lesion and reversible inactivation studies demonstrating that the IP is required for acquisition of delay conditioning across multiple species including rabbits (Clark, Zhang, & Lavond, 1992; Krupa et al., 1993; Lavond, Hembree, & Thompson, 1985; Lincoln, McCormick, & Thompson, 1982; Nordholm, Thompson, Dersarkissian, & Thompson, 1993; Pacheco-Calderon et al., 2012; Sears and Steinmetz, 1990; Weisz and LoTurco, 1988), rats (Freeman, Carter, & Stanton, 1995; Lee and Kim, 2004), and mice (Chen, Bao, Lockard, Kim, & Thompson, 1996; Porras-Garcia et al., 2010), with evidence extending to eyeblink studies in humans with cerebellar damages (Daum et al., 1993). However, of note, there is still some controversy regarding whether the IP is necessary for acquisition versus performance of eyeblink CRs and whether the cerebellar cortex can support acquisition in the absence of the IP in multiple species (Jimenez-Diaz, Navarro-Lopez, Gruart, & Delgado-Garcia, 2004; Sakamoto and Endo, 2010; Welsh and Harvey, 1991), including humans (Gerwig et al., 2003, 2010). In addition, recent work suggests that extracerebellar areas interacting with the IP such as the motor cortex and red nucleus may play a more active role in the acquisition and generation of CRs than traditionally thought (Ammann et al., 2016; Pacheco-Calderon et al., 2012), which opens up the possibility that the IP could also be modulating other brain areas capable of developing eyeblink conditioning-related plasticity.

    • Pronounced reduction of acquisition of conditioned eyeblink responses in young adults with focal cerebellar lesions impedes conclusions on the role of the cerebellum in extinction and savings

      2016, Neuropsychologia
      Citation Excerpt :

      The US and the CS were presented on the corresponding side in all matched controls except one (con-13 in Table 1). In paired and CS-only trials CRs were semiautomatically identified in the CS-US interval using custom made software, see (Gerwig et al., 2010) for details. Responses earlier than 150 ms after CS onset were regarded as reflexive responses to the tone (i.e. alpha responses) and not conditioning-related (Woodruff-Pak et al., 1996).

    • Associative Learning in the Cerebellum

      2015, International Encyclopedia of the Social & Behavioral Sciences: Second Edition
    View all citing articles on Scopus
    View full text