Mechanisms of human cerebellar dysmetria: experimental evidence and current conceptual bases
Mario Manto, Mario Manto
Abstract
The human cerebellum contains more neurons than any other region in the brain and is a major actor in motor control. Cerebellar circuitry is unique by its stereotyped architecture and its modular organization. Understanding the motor codes underlying the organization of limb movement and the rules of signal processing applied by the cerebellar circuits remains a major challenge for the forthcoming decades. One of the cardinal deficits observed in cerebellar patients is dysmetria, designating the inability to perform accurate movements. Patients overshoot (hypermetria) or undershoot (hypometria) the aimed target during voluntary goal-directed tasks. The mechanisms of cerebellar dysmetria are reviewed, with an emphasis on the roles of cerebellar pathways in controlling fundamental aspects of movement control such as anticipation, timing of motor commands, sensorimotor synchronization, maintenance of sensorimotor associations and tuning of the magnitudes of muscle activities. An overview of recent advances in our understanding of the contribution of cerebellar circuitry in the elaboration and shaping of motor commands is provided, with a discussion on the relevant anatomy, the results of the neurophysiological studies, and the computational models which have been proposed to approach cerebellar function.
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References
- Porrill J, Dean P. Silent synapses, LTP, and the indirect parallel-fibre pathway: computational consequences of optimal cerebellar noise-processing. PLoS Comput Biol. 2008;4:e1000085.
- Stein RB, Gossen ER, Jones KE. Neuronal variability: noise or part of the signal? Nature Rev Neurosci. 2005;6:389–397.
- Ramnani N. The primate cortico-cerebellar system: anatomy and function. Nat Rev Neurosci. 2006;7:511–522.
- Manto M, Bastian AJ. Cerebellum and the deciphering of motor coding. Cerebellum. 2007;6:3–6.
- Allen GI, Tsukahara N. Cerebrocerebellar communication systems. Physiol Rev. 1974;54:957–1006.
- Kelly RM, Strick PL. Cerebellar loops with motor cortex and prefrontal cortex of a nonhuman primate. J Neurosci. 2003;23:8432–8444.
- Timmann D, Daum I. Cerebellar contributions to cognitive functions: A progress report after two decades of research. Cerebellum. 2007;6:159–162.
- Haines DE, Manto MU. Clinical symptoms of cerebellar disease and their interpretation. Cerebellum. 2007;6:360–374.
- Holmes G. The cerebellum of man. The Hughlings Jackson memorial lecture. Brain. 1939;62:1–30.
- Hallett M, Massaquoi S. Physiologic studies of dysmetria in patients with cerebellar deficits. Can J Neurol Sci. 1993;20 Suppl 3:S83–S92.
- Massaquoi SG, Hallett M. Kinematics of initiating a two-joint arm movement in patients with cerebellar ataxia. Can J Neurol Sci. 1996;23:3–14.
- Topka H, Konczak J, Schneider K, Boose A, Dichgans J. Multijoint arm movements in cerebellar ataxia: abnormal control of movement dynamics. Exp Brain Res. 1998;119:493–503.
- Bastian AJ, Martin TA, Keating JG. Cerebellar ataxia: abnormal control of interaction torques across multiple joints. J Neurophysiol. 1996;76:492–509.
- Brown SH, Hefter H, Mertens M, Freund HJ. Disturbances in human arm movement trajectory due to mild cerebellar dysfunction. J Neurol Neurosurg Psychiatry. 1990;53:306–313.
- Day BL, Thompson PD, Harding AE, Marsden CD. Influence of vision on upper limb reaching movements in patients with cerebellar ataxia. Brain. 1998;121:357–372.
- Ito M. Cerebellar circuitry as a neuronal machine. Prog Neurobiol. 2006;78:272–303.
- Yarom Y, Cohen D. The olivocerebellar system as a generator of temporal patterns. Ann N Y Acad Sci. 2002;978:122–134.
- Manto M, Haines D, Yoshida M, Obata K, Ito M. Cerebellar classics I. Cerebellum. 2007:102–105.
- Colin F, Ris L, Godaux E. Neuroanatomy of the cerebellum. In: Manto M, Pandolfo M, editor. The cerebellum and its disorders. Cambridge University Press, Cambridge, UK; 2002. pp. 6–29.
- Zagon IS, McLaughlin PJ, Smith S. Neural populations in the human cerebellum: estimations from isolated cell nuclei. Brain Res. 1977;127:279–82.
- Brunel N, Hakim V, Isope P, Nodal JP, Barbour JP. Optimal information storage and the distribution of synaptic weights: perceptron versus Purkinje cells. Neuron. 2004;43:745–757.
- Schweighofer N, Doya K, Lay F. Unsupervised learning of granule cell sparse codes enhances cerebellar adaptative control. Neuroscience. 2001;103:35–50.
- Mugnaini E. The length of cerebellar parallel fibers in chicken and rhesus monkey. J Comp Neurol. 1983;220:7–15.
- Eccles JC, Ito M, Szenthagothai J. The cerebellum as a neuronal machine. New York, Heidelberg, Springer-Verlag; 1967.
- Bastian , Thach . Structure and function of the cerebellum. In: Manto M, Pandolfo M, editor. The Cerebellum and its disorders. Cambridge University Press, Cambridge; 2002. pp. 49–66.
- Thach WT. On the mechanism of cerebellar contributions to cognition. Cerebellum. 2007;6:163–167.
- Orioli PJ, Strick PL. Cerebellar connections with the motor cortex and the arcuate premotor area: an analysis employing retrograde transneuronal transport of WGA-HRP. J Comp Neurol. 1989;288:612–626.
- Asanuma C, Thach WT, Jones EG. Cytoarchitectonic delineation of the ventral lateral thalamic region in the monkey. Brain Res. 1983;286:219–235.
- Asanuma C, Thach WT, Jones EG. Distribution of cerebellar terminations and their relation to other afferent terminations in the ventral lateral thalamic region of the monkey. Brain Res. 1983;286:237–265.
- Sanchez M, Sillitoe RV, Attwell PJE, Ivarsson M, Rahman S, Yeo CH, Hawkes R. Compartmentation of the rabbit cerebellar cortex. J Comp Neurol. 2002;444:159–173.
- Gould BB, Graybiel AM. Afferents to the cerebellar cortex in the cat: evidence for an intrinsic pathway leading from the deep nuclei to the cortex. Brain Res. 1976;110:601–611.
- Schmahmann JD. The cerebellum and cognition. Academic Press, San Diego; 1997.
- Middleton FA, Strick PL. Cerebellar output channels. In: Schmahmann JD, editor. The cerebellum and cognition. Academic Press, San Diego; 1997. pp. 61–82.
- Llinas R, Yarom Y. Electrophysiology of mammalian inferior olivary neurons in vitro. Different types of voltage-dependent ionic conductances. J Physiol (Lond) 1981;315:549–567.
- Bauswein E, Kolb FP, Leimbeck B, Rubia FJ. Simple and complex spike activity of cerebellar Purkinje cells during active and passive movements in the awake monkey. J Physiol. 1983;339:379–94.
- Harvey RJ, Porter R, Rawson JA. The natural discharges of Purkinje cells in paravermal regions of lobules V and VI of the monkey's cerebellum. J Physiol (Lond) 1977;271:515–536.
- Ito M. Long-term depression. Annu Rev Neurosci. 1989;12:85–102.
- Montgomery JM, Selcher JC, Hanson JE, Madison DV. Dynamin-dependent NMDAR endocytosis during LTD and its dependence on synaptic state. BMC Neurosci. 2005;6:48.
- Lev-Ram V, Mehta SB, Kleinfeld D, Tsien RY. Reversing cerebellar long-term depression. Proc Natl Acad Sci USA. 2003;100:15989–15993.
- Buttner U, Fuchs AF, Markert-Schwab G, Buckmaster P. Fastigial nucleus activity in the alert monkey during slow eye and head movements. J Neurophysiol. 1991;65:1360–1371.
- Fuchs AF, Robinson FR, Straube A. Participation of the caudal fastigial nucleus in smooth-pursuit eye movements. I. Neuronal activity. J Neurophysiol. 1994;72:2714–2728.
- Vilis T, Hore J. Effects of changes in mechanical state of limb on cerebellar intention tremor. J Neurophysiol. 1977;40:1214–1224.
- Smith AM, Bourbonnais D. Neuronal activity in cerebellar cortex related to control of prehensile force. J Neurophysiol. 1981;45:286–303.
- Frysinger RC, Bourbonnais D, Kalaska JF, Smith AM. Cerebellar cortical activity during antagonist cocontraction and reciprocal inhibition of forearm muscles. J Neurophysiol. 1984;51:32–49.
- Vilis T, Hore J. Central neuronal mechanisms contributing to cerebellar tremor produced by limb perturbations. J Neurophysiol. 1980;43:279–291.
- Soechting JF, Burton JE, Onoda N. Relationships between sensory input, motor output and unit activity in interpositus and red nuclei during intentional movement. Brain Res. 1978;152:65–79.
- Schieber MH, Thach WT Jr. Trained slow tracking II. Bidirectional discharge patterns of cerebellar nuclear, motor cortex, and spindle afferent neurons. J Neurophysiol. 1985;54:1228–1270.
- Gilman S. The mechanism of cerebellar hypotonia. Brain. 1969;92:621–638.
- Oulad Ben Taib N, Laute MA, Pandolfo M, Manto MU. Interaction between repetitive stimulation of the sciatic nerve and functional ablation of cerebellar nucleus interpositus in the rat. Cerebellum. 2004;3:21–26.
- Monzée J, Drew T, Smith AM. Effects of muscimol inactivation of the cerebellar nuclei on precision grip. J Neurophysiol. 2004;91:1240–1249.
- Monzée J, Smith AM. Responses of cerebellar interpositus neurons to predictable perturbations applied to an object held in a precision grip. J Neurophysiol. 2004;91:1230–1239.
- Hore J, Flament D. Evidence that a disordered servo-like mechanism contributes to tremor in movements during cerebellar dysfunction. J Neurophysiol. 1986;56:123–136.
- Topka H, Massaquoi SG. Pathophysiology of clinical cerebellar signs. In: Manto M, Pandolfo M, editor. The Cerebellum and its disorders. Cambridge University Press, Cambridge; 2002. pp. 121–135.
- Flament D, Hore J. Movement and electromyographic disorders associated with cerebellar dysmetria. J Neurophysiol. 1986;55:1221–1233.
- Topka H, Mescheriakov S, Boose A, et al. A cerebellar-like terminal and postural tremor induced in normal man by transcranial magnetic stimulation. Brain. 1999;122:1551–1562.
- Thach WT. Correlation of neural discharge with pattern and force of muscular activity, joint position, and direction of intended next movement in motor cortex and cerebellum. J Neurophysiol. 1978;41:654–678.
- Mason CR, Miller LE, Baker JF, Houk JC. Organization of reaching and grasping movements in the primate cerebellar. J Neurophysiol. 1998;79:537–554.
- Trouche E, Beaubaton D. Initiation of a goal-directed movement in the monkey. Exp Brain Res. 1980;40:311–321.
- Di Lazzaro V, Restuccia D, Nardone R, Leggio MG, Oliviero A, Profice P, Tonali P, Molinari M. Motor cortex changes in a patient with hemicerebellectomy. Electroencephalogr Clin Neurophysiol. 1995;97:259–263.
- Oulad Ben Taib N, Manto M. Effects of trains of high-frequency stimulation of the premotor/supplementary motor area on conditioned corticomotor responses in hemicerebellectomized rats. Exp Neurol. 2008;212:157–165.
- Ugawa Y, Uesaka Y, Terao Y, Hanajima R, Kanazawa I. Magnetic stimulation over the cerebellum in humans. Ann Neurol. 1995;37:703–713.
- Wessel K, Tegenthoff M, Vorgerd M, Otto V, Nitsche MF, Malin JP. Enhancement of inhibitory mechanisms in the motor cortex of patients with cerebellar degeneration: a study with transcranial magnetic brain stimulation. Electroencephalogr Clin Neurophysiol. 1996;101:273–280.
- Liepert J, Kucinski T, Tuscher O, Pawlas F, Baumer T, Weiller C. Motor cortex excitability after cerebellar infarction. Stroke. 2004;35:2484–2488.
- Tamburin S, Fiaschi A, Marani S, Andreoli A, Manganotti P, Zanette G. Enhanced intracortical inhibition in cerebellar patients. J Neurol Sci. 2004;217:205–210.
- Oliveri M, Torriero S, Koch G, Salerno S, Petrosini L, Caltagirone C. The role of transcranial magnetic stimulation in the study of cerebellar cognitive function. Cerebellum. 2007;6:95–101.
- Di Lazzaro V, Restuccia D, Molinari M, Leggio MG, Nardone R, Fogli D. Excitability of the motor cortex to magnetic stimulation in patients with cerebellar lesions. J Neurol Neurosurg Psychiatry. 1994;57:108–120.
- Restuccia D, Valeriani M, Barba C, Le Pera D, Capecci M, Filippini V, Molinari M. Functional changes of the primary somatosensory cortex in patients with unilateral cerebellar lesions. Brain. 2001;124:757–768.
- Boggio PS, Castro LO, Savagim EA, Braite R, Cruz VC, Rocha RR, Rigonatti SP, Silva MTA, Fregni F. Enhancement of non-dominant hand motor function by anodal transcranial direct current stimulation. Neurosci Lett. 2006;404:232–236.
- Nitsche MA, Seeber A, Frommann K, Klein CC, Rochford C, Nitsche MS, Fricke K, Liebetanz D, Lang N, Antal A, Paulus W, Tergau F. Modulating parameters of excitability during and after transcranial direct current stimulation of the human motor cortex. J Physiol (Lond) 2005;568:291–303.
- Oulad Ben Taib N, Manto M. Trains of transcranial DC stimulation antagonize motor cortex hypoexcitability induced by acute hemicerebellectomy. J Neurosurg.
- Fujita M. Adaptive filter model of the cerebellum. Biol Cybern. 1982;45:195–206.
- Wolpert DM, Miall RC, Kawato M. Internal models in the cerebellum. Trends Cogn Sci. 1998;2:338–347.
- Eccles JC, Ito M, Szentagothai J. The cerebellum as a neuronal machine. Springer-Verlag, Berlin; 1967.
- Braintenberg V. Is the cerebellar cortex a biological clock in the millisecond range? Prog Brain Res. 1967;25:334–346.
- Ivry RB, Spencer RM. The neural representation of time. Curr Opin Neurobiol. 2004;14:225–232.
- Massaquoi S, Slotine JE. The intermediate cerebellum may function as a wave-variable processor. Neurosci Lett. 1996;215:60–64.
- Bower JM. Control of sensory data acquisition. Int Rev Neurobiol. 1997;41:489–513.
- Sejnowski TJ. Storing covariance with nonlinearly interacting neurons. J Math Biol. 1977;4:303–321.
- Kawato M, Kuroda T, Imamizu H, Nakano E, Miyauchi S, Yoshioka T. Internal forward models in the cerebellum: FMRI study on grip force and load force coupling. Prog Brain Res. 2003;142:171–188.
- Miall RC, Christensen LO, Cain O, Stanley J. Disruption of state estimation in the human lateral cerebellum. Plos Biol. 2007;5:e316.
- Morton SM, Bastian AJ. Mechanisms of cerebellar gait ataxia. Cerebellum. 2007;6:79–86.
- Ioffe ME, Chernikova LA, Ustinova KI. Role of cerebellum in learning postural tasks. Cerebellum. 2007;6:87–94.
- Roitman AV, Pasalar S, Johnson MT, Ebner TJ. Position, direction of movement, and speed tuning of cerebellar Purkinje cells during circular manual tracking in monkey. J Neurosci. 2005;25:9244–9257.
- Fu QG, Flament D, Coltz JD, Ebner TJ. Relationship of cerebellar Purkinje cell simple spike discharge to movement kinematics in the monkey. J Neurophysiol. 1997;78:478–491.
- Bell CC, Han V, Sawtell NB. Cerebellum-like structures and their implications for cerebellar function. Annu Rev Neurosci. 2008
- Nowak DA, Topka H, Timmann D, Boecker H, Hermsdorfer J. The role of the cerebellum for predictive control of grasping. Cerebellum. 2007;6:7–17.
- Bodznick D, Montgomery JC, Carey M. Adaptive mechanisms in the elasmobranch hindbrain. J Exp Biol. 1999;202:1357–1364.
- Maschke M, Gomez CM, Ebner TJ, Konczak J. Hereditary cerebellar ataxia progressively impairs force adaptation during goal-directed arm movements. J Neurophysiol. 2004;91:230–238.
- Shidara M, Kawano K, Gomi H, Kawato M. Inverse-dynamics model eye movement control by Purkinje cells in the cerebellum. Nature. 1993;365:50–52.
- Yamamoto K, Kawato M, Kotosaka S, Kitazawa S. Encoding of movement dynamics by Purkinje cell simple spike activity during fast arm movements under resistive and assistive force fields. J Neurophysiol. 2007;97:1588–1599.
- Pasalar S, Roitman AV, Durfee WK, Ebner TJ. Force field effects on cerebellar Purkinje cell discharge with implications for internal models. Nat Neurosci. 2006;9:1404–1411.
- Schweighofer N, Arbib MA, Kawato M. Role of the cerebellum in reaching movements in human. I. Distributed inverse dynamics control. Eur J Neurosci. 1998;10:86–94.
- Bernstein N. The co-ordination and regulation of movement. Pergamon Press, Oxford, United Kingdom; 1967.
- Hannaford B, Stark L. Roles of the elements of the triphasic control signal. Exp Neurol. 1985;90:619–634.
- Hallett M, Shahani BT, Young RR. EMG analysis of stereotyped voluntary movements in man. J Neurol Neurosurg Psychiatry. 1975;38:1154–1162.
- Manto M, Godaux E, Jacquy J. Detection of silent cerebellar lesions by increasing the inertial load of the moving hand. Ann Neurol. 1995;37:344–350.
- Manto M, Godaux E, Jacquy J, Hildebrand J. Cerebellar hypermetria associated with a selective decrease in the rate of rise of antagonist activity. Ann Neurol. 1996;39:271–274.
- Gottlieb GL. Muscle activation patterns during two types of voluntary single-joint movement. J Neurophysiol. 1998;80:1860–1867.
- Feldman AG. Superposition of motor program. I. Rhythmic forearm movements in man. Neuroscience. 1980;5:81–90.
- Todorov E. Direct cortical control of muscle activation in voluntary arm movements: a model. Nature Neurosci. 2000;3:391–398.
- Morasso P, Mussa Ivaldi FA. Trajectory formation and handwriting: a computational model. Biol Cybern. 1982;45:131–142.
- Manto M. Cerebellar ataxias. In: Hallett M, editor. Movement Disorders Handbook of clinical neurophysiology. Vol. 1. 2003. pp. 491–520.
- Friedmann HH, Noth J, Diener HC, Bacher M. Long latency EMG responses in hand and leg muscles: cerebellar disorders. J Neurol Neurosurg Psychiatry. 1987;50:71–77.
- Timmann D, Watts S, Hore J. Failure of cerebellar patients to time finger opening precisely causes ball high-low inaccuracy in overarm throws. J Neurophysiol. 1999;82:103–114.
- Keating JG, Thach WT. Nonclock behaviour of inferior olive neurons: interspike interval of Purkinje cell complex spike discharge in the awake behaving monkey is random. J Neurophysiol. 1995;73:1329–1340.
- Ivry RB, Keele SW, Diener HC. Dissociation of the lateral and medial cerebellum in movement timing and movement execution. Exp Brain Res. 1988;73:167–180.
- Molinari M, Leggio MG, Thaut MH. The cerebellum and neural networks for rhythmic sensorimotor synchronization in the human brain. Cerebellum. 2007;6:18–23.
- Gilbert PFC, Thach WT. Purkinje cell activity during motor learning. Brain Res. 1977;128:309–328.
- Kitazawa S, Kimura T, Yin PB. Cerebellar complex spikes encode both destinations and errors in arm movements. Nature. 1998;392:494–497.
- Gerwig M, Kolb FP, Timmann D. The involvement of the human cerebellum in eyeblink conditioning. Cerebellum. 2007;6:38–57.
- Christian KM, Thompson RF. Neural substrates of eyeblink conditioning : acquisition and retention. Learn Mem. 2003;10:427–455.
- De Zeeuw CI, Yeo CH. Time and tide in cerebellar memory formation. Curr Opin Neurobiol. 2005;15:667–674.
- McCormick DA, Clark GA, Lavond DG, Thompson RF. Initial localization of the memory trace for a basic form of learning. Proc Natl Acad Sci USA. 1982;79:2731–2735.
- Hirano T. Motor control mechanism by the cerebellum. Cerebellum. 2006;5:296–300.
- Manto M, Nowak D, Schutter DLJG. Coupling between cerebellar hemispheres and sensory processing. Cerebellum. 2006;5:187–188.
- Soteropoulos DS, Baker SN. Cortico-cerebellar coherence during a precision grip task in the monkey. J Neurophysiol. 2006;95:1194–1206.
- Manzoni D. The cerebellum and sensorimotor coupling: looking at the problem from the perspective of vestibular reflexes. Cerebellum. 2007;6:24–37.
- Pellionisz AJ. Tensorial brain theory in cerebellar modelling. In: Bloedel JR, Dichgans J, Precht W, editor. Cerebellar functions. New York, Springer-Verlag; 1985. pp. 201–229. 100.
- Niemeyer G, Slotine JE. Stable adaptative teleoperation. IEEE Ocean Eng. 1991;16:152–162.
- Merton PA. Speculations on the servo-control of movement. In: Malcom JL, Gray AB, Wolstenholme GAW, editor. The spinal cord. Little, Brown & Co, Boston; 1953.
- Morton SM, Bastian AJ. Cerebellar contributions to locomotor adaptations during splitbelt treadmill walking. J Neurosci. 2006;26:9107–9116.
- Horak FB, Diener HC. Cerebellar control of postural scaling and central set. J Neurophysiol. 1994;72:479–493.
- Lang CE, Bastian AJ. Cerebellar subjects show impaired adaptation of anticipatory EMG during catching. J Neurophysiol. 1999;82:2108–2119.
- Eahart GM, Bastian AJ. Cerebellar gait ataxia: selection and coordination of human locomotor forms. J Neurophysiol. 2001;85:759–769.
- Reisman DS, Block HJ, Bastian AJ. Interlimb coordination during locomotion: what can be adapted and stored? J Neurophysiol. 2005;94:2403–2415.
- Fellows SJ, Ernst J, Schwarz M, Töpper R, Noth J. Precision grip in cerebellar disorders in man. Clin Neurophysiol. 2001;112:1793–1802.
- Rocon E, Manto M, Pons J, Camut S, Belda JM. Mechanical suppression of essential tremor. Cerebellum. 2007;6:73–78.
- Shadmehr R, Krakauer JW. A computational neuroanatomy for motor control. Exp Brain Res. 2008;185:359–381.
- Scovil CY, Ronsky JL. Sensitivity of a Hill-based muscle model to perturbations in model parameters. J Biomech. 2006;39:2055–2063.
- Bastian AJ. Learning to predict the future: the cerebellum adapts feedforward movement control. Curr Opin Neurobiol. 2006;16:645–649.
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