Cerebellar activation during leg withdrawal reflex conditioning: an fMRI study

OBJECTIVE The aim of the present study was to examine cerebellar areas related to conditioning of the nociceptive leg withdrawal reflex using event-related functional magnetic resonance imaging (fMRI). Because of the aversive nature of the unconditioned stimulus effects of accompanying fear conditioning were expected. METHODS In 20 healthy adult subjects leg withdrawal reflex conditioning was performed using a standard delay protocol during MR-scanning. Electromyographic recordings from the anterior tibial and biceps femoris muscles were used to quantify conditioned responses. Fear-related changes of heart rate were assessed. RESULTS In the group of all subjects a significant increase of cerebellar activation was found in the anterior and posterior vermis. In the group of subjects (n=9) who showed conditioned leg withdrawal responses cerebellar activation was more pronounced in parts of the anterior vermis, which correspond to the known leg representation. In the group of subjects (n=11) who did not develop conditioned responses cerebellar activation was more pronounced in the posterolateral hemispheres. Changes of heart rate, however, did not significantly differ between groups. CONCLUSIONS Results suggest that areas within the anterior vermis are involved in conditioning of the leg withdrawal response. The present results, however, do not allow to differentiate between motor performance, learning or timing-related processes. Areas in the posterior vermis and cerebellar hemispheres may be related to concomitant fear conditioning. SIGNIFICANCE Results of the present event-related fMRI study suggest involvement of the human cerebellum in conditioning of the nociceptive leg withdrawal response.

[1]  Germund Hesslow,et al.  Cerebellum and conditioned reflexes , 1998, Trends in Cognitive Sciences.

[2]  Johannes Drepper,et al.  Limb flexion reflex-related areas in human cerebellum , 2002, Neuroreport.

[3]  WF Supple,et al.  The anterior cerebellar vermis: essential involvement in classically conditioned bradycardia in the rabbit , 1993, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[4]  P. Obrist,et al.  Heart rate during conditioning in humans: effect of varying the interstimulus (CS-UCS) interval. , 1967, Journal of experimental psychology.

[5]  D. Powell,et al.  Classical Conditioning of Autonomic and Somatomotor Responses and Their Central Nervous System Substrates , 2002 .

[6]  A. McIntosh,et al.  Large-scale functional connectivity in associative learning: interrelations of the rat auditory, visual, and limbic systems. , 1998, Journal of neurophysiology.

[7]  Richard Apps,et al.  Central regulation of cerebellar climbing fibre input during motor learning , 2002, The Journal of physiology.

[8]  H. Diener,et al.  Involvement of the human cerebellum in fear-conditioned potentiation of the acoustic startle response: a PET study , 2002, Neuroreport.

[9]  E. Adrian AFFERENT AREAS IN THE CEREBELLUM CONNECTED WITH THE LIMBS , 1943 .

[10]  Scott T. Grafton,et al.  Functional anatomy of human eyeblink conditioning determined with regional cerebral glucose metabolism and positron-emission tomography. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[11]  A R McIntosh,et al.  Lateralization and behavioral correlation of changes in regional cerebral blood flow with classical conditioning of the human eyeblink response. , 1997, Journal of neurophysiology.

[12]  Brunello Ghelarducci,et al.  Effects of early cerebellar removal on the classically conditioned bradycardia of adult rabbits , 1996, Experimental Brain Research.

[13]  S. Kiebel,et al.  Multiple somatotopic representations in the human cerebellum. , 1999, Neuroreport.

[14]  Joseph E LeDoux,et al.  Human Amygdala Activation during Conditioned Fear Acquisition and Extinction: a Mixed-Trial fMRI Study , 1998, Neuron.

[15]  Alan C. Evans,et al.  MRI Atlas of the Human Cerebellum , 2000 .

[16]  J. Andersson,et al.  Fear conditioning and brain activity: a positron emission tomography study in humans. , 2000, Behavioral neuroscience.

[17]  M. Mauk,et al.  Cerebellar function: Coordination, learning or timing? , 2000, Current Biology.

[18]  D Timmann,et al.  Cerebellar responses evoked by nociceptive leg withdrawal reflex as revealed by event-related FMRI. , 2003, Journal of neurophysiology.

[19]  L. Sebastiani,et al.  Purkinje cell responses in the anterior cerebellar vermis during Pavlovian fear conditioning in the rabbit. , 1993, Neuroreport.

[20]  J. Gabrieli,et al.  Functional Mapping of Human Learning: A Positron Emission Tomography Activation Study of Eyeblink Conditioning , 1996, The Journal of Neuroscience.

[21]  J. Schouenborg,et al.  Topography and nociceptive receptive fields of climbing fibres projecting to the cerebellar anterior lobe in the cat. , 1991, The Journal of physiology.

[22]  R. N. Leaton,et al.  Lesions of the cerebellar vermis and cerebellar hemispheres: effects on heart rate conditioning in rats. , 1990, Behavioral neuroscience.

[23]  D Timmann,et al.  Comparison of eyeblink conditioning in patients with superior and posterior inferior cerebellar lesions. , 2003, Brain : a journal of neurology.

[24]  Todd B. Parrish,et al.  Electromyography as a Recording System for Eyeblink Conditioning with Functional Magnetic Resonance Imaging , 2002, NeuroImage.

[25]  R. N. Leaton,et al.  Cerebellar vermis: essential for classically conditioned bradycardia in the rat , 1990, Brain Research.

[26]  L. Sebastiani,et al.  Influence of the cerebellar posterior vermis on the acquisition of the classically conditioned bradycardic response in the rabbit , 2005, Experimental Brain Research.

[27]  J Schouenborg,et al.  The postsynaptic dorsal column pathway mediates cutaneous nociceptive information to cerebellar climbing fibres in the cat. , 1991, The Journal of physiology.

[28]  T. J. Voneida The effect of brachium conjunctivum transection on a conditioned limb response in the cat , 2000, Behavioural Brain Research.

[29]  D. Timmann Classically conditioned withdrawal reflex in cerebellar patients , 2000 .

[30]  Jan Voogd,et al.  The anatomy of the cerebellum , 1998, Trends in Cognitive Sciences.

[31]  F. Kolb,et al.  Classical conditioning of the human flexion reflex. , 1996, Electroencephalography and clinical neurophysiology.

[32]  M. Glickstein,et al.  Cerebellum and Neuronal Plasticity , 1987, NATO ASI Series.

[33]  M. Torrens Co-Planar Stereotaxic Atlas of the Human Brain—3-Dimensional Proportional System: An Approach to Cerebral Imaging, J. Talairach, P. Tournoux. Georg Thieme Verlag, New York (1988), 122 pp., 130 figs. DM 268 , 1990 .

[34]  C. Weiller,et al.  Cerebellar activation during classical conditioning of the human flexion reflex: a PET study. , 1996, Neuroreport.

[35]  R. Dolan,et al.  Classical fear conditioning in functional neuroimaging , 2000, Current Opinion in Neurobiology.

[36]  H. Diener,et al.  Classically conditioned withdrawal reflex in cerebellar patients. 1. Impaired conditioned responses , 2000, Experimental Brain Research.

[37]  B. Schreurs,et al.  A functional anatomical study of associative learning in humans. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[38]  R. Snider,et al.  RECEIVING AREAS OF THE TACTILE, AUDITORY, AND VISUAL SYSTEMS IN THE CEREBELLUM , 1944 .

[39]  J. R. Bloedel,et al.  Conditioned and unconditioned forelimb reflex systems in the cat: involvement of the intermediate cerebellum , 1997, Experimental Brain Research.

[40]  N Ramnani,et al.  Learning- and expectation-related changes in the human brain during motor learning. , 2000, Journal of neurophysiology.

[41]  O. Oscarsson,et al.  Spatial Distribution of Climbing and Mossy Fibre Inputs into the Cerebellar Cortex , 1976 .

[42]  R. Dolan,et al.  A subcortical pathway to the right amygdala mediating "unseen" fear. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[43]  M. Erb,et al.  Sensorimotor mapping of the human cerebellum: fMRI evidence of somatotopic organization , 2001, Human brain mapping.

[44]  Richard B. Ivry,et al.  Cerebellar involvement in eyeblink classical conditioning in humans. , 1996 .

[45]  Comparative Study of Cerebellar Somatosensory Representations the Importance of Micromapping and Natural Stimulation , 1987 .

[46]  Michael Forsting,et al.  Eyeblink‐related areas in human cerebellum as shown by fMRI , 2002, Human brain mapping.