Mechanisms of human cerebellar dysmetria: experimental evidence and current conceptual bases

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.

Figure 1

Cerebellar hypermetria. Superimposition of 9 fast wrist flexion movements in a control subject [A] and a cerebellar patient [B]. Movements (MVT) are accurate in A and are hypermetric in B (overshoot of the target). Aimed target (dotted lines) located at 0.4 rad from the start position corresponding to a neutral position of the joint. The target is visually displayed.

Figure 2

Effects of increasing velocities on kinematics of the upper limb pointing movements in a control subject (upper panels) and a cerebellar patient (lower panels). Subjects are seated and comfortably restrained in order to allow only shoulder and elbow movements. They are asked to perform a vertical pointing movement towards a fixed target at various speeds. The target is located in front of the subjects at a distance of 85% of total arm length. In the patient, deficits in angular motion are enhanced with increasing velocities, especially the increased angular motion of elbow resulting in overshoot (hyperextension of the elbow). Black lines: angular position of the elbow; grey lines: angular position of the shoulder. Abbreviations: sh: shoulder angle, elb: elbow angle.

Figure 3

Asymmetry in kinematics of fast wrist flexion movements in cerebellar patients exhibiting hypermetria. Values correspond to ratios of Acceleration Peaks divided by Deceleration Peaks. Mean +/- SD and individual ratios are shown. Data from n = 7 ataxic patients; mean age: 53.2 +/- 5.7 years. Control group: n = 7 subjects; mean age: 54.5 +/- 6.1 years. Aimed target: 15 degrees; n = 10 movements per subject.

Figure 4

Wiring diagram of the cerebellar circuitry. Purkinje neurons are the sole output of the cerebellar cortex. Basket cells supply the inhibitory synapses via a synapse called "pinceau", stellate cells supply the inhibition to Purkinje cell dendrites. Lugaro cells are activated by serotoninergic fibers and inhibit Golgi cells. In addition to the illustrated serotoninergic afferences, cerebellar cortex receives other aminergic inputs (acetylcholine, dopamine, norepinephrine, histamine) or peptidergic projections (peptides such as neurotensin). These fibers project sparsely throughout the granular and molecular layers to contact directly the Purkinje neurons and other cerebellar neurons. Abbreviations: ST: serotoninergic fiber, pf: parallel fiber, Gran. c: granule cell, MF: mossy fiber, br. c: unipolar brush cell, CF: climbing fiber, IO: inferior olive, Gc: Golgi cell, Lc: Lugaro cell, Bc: basket cell, Sc: stellate cell, PN: Purkinje neuron; CN: cerebellar nucleus, mf: recurrent mossy fiber from nuclear cell.

Figure 5

Multiple body maps in the cerebellum. Each cerebellar nucleus has a complete map of the body, with head located posteriorly, limbs medially and trunk laterally. Thanks to the parallel fibers (pf, issued from granule cells) linking together Purkinje neurons (PN) projecting to distinct body areas, myotomes can be interconnected during motor tasks. Parallel fibers are long enough to link together Purkinje neurons projecting to different portions within one nuclear body map, and multiple maps. The contacts between parallel fibers and the dendrites of cortical inhibitory interneurons are not illustrated. Adapted from Thach, 2007.

Figure 6

Comparison of anatomical connections of the vermal zone (A), the intermediate zone (B) and the lateral zone of the cerebellum (C). The midline zone and the intermediate zone receive direct informations from the spinal cord, unlike the lateral cerebellum. Abbreviations: IOC: inferior olivary complex, LVN: lateral vestibular nucleus, FN: fastigial nucleus, NI: nucleus interpositus, DN: dentate nucleus.

Figure 7

A: According to the model of Allen and Tsukahara (1974), the intermediate zone of the cerebellar hemisphere contributes to movement execution by monitoring actual sensory feedback and processing error signals that compensate for prediction errors in movement planning. The lateral zone of the cerebellar hemisphere participates in the planning and programming of movements by integrating sensory information. B: Output channels in the dentate nucleus. Distinct areas of the dentate nucleus project predominantly upon different regions of the contralateral cerebral cortex, via thalamic nuclei (MD/VLc: medial dorsal/ventralis lateral pars caudalis nuclei, 'area X', VPLo: nucleus ventralis posterior lateralis pars oralis). Dorsal portions of the dentate nucleus project mainly upon area 4.

Figure 8

Decreased excitability of the motor cortex contralaterally to the ablation of the left hemicerebellum in a rat, as revealed by the study of recruitment curves of corticomotor responses in the gastrocnemius muscle. Recordings in the gastrocnemius muscle following incremental electrical stimulation of the motor cortex. Plots correspond to the amplitude of motor evoked potentials as a function of stimulus intensity. Filled triangles: stimulation of left motor cortex, open triangles: stimulation of right motor cortex. Fitting with a sigmoidal curve (3 parameters). 95% prediction band and 95% confidence band are illustrated. Amplitudes of recorded motor evoked potentials (MEPs) are expressed in mV.

Figure 9

Forward model-based control scheme (top panel) and inverse model-based control scheme (middle panel). Forward model: the message dedicated to the peripheral motor apparatus A is sent with an efference copy transmitted to the cerebellum A'. Instructions originating from higher motor centers (such as the premotor cortex) reach a comparator (grey circle). The comparator drives the motor cortex (a), which in turns drives lower motor centers in the brainstem and spinal cord. Efference copies are used to perform future predictions. Cerebellar microcircuits are necessary to learn how to make appropriately these predictive codes. Inverse model: A corresponds to the motor apparatus/control object. Cerebellar cortex working in parallel with the motor cortex and forming an internal model with a transfer function a' reciprocally equal to the dynamics of the control object (a' = 1/A). The input to the cerebellum is the desired trajectory, the output is the motor command. The bottom panel illustrates the model of the wave-variable processor for the intermediate cerebellum and the spinal cord gray matter. These structures contribute to motion control by processing control signals as wave variables. These wave variables are combinations of forward and return signals ensuring stable exchanges despite destabilizing signal transmission delays (adapted from [76].

Figure 10

Communication flows for information processing in forward models of motor coding. Cerebellar modules receive an efference copy of motor commands via the corticopontocerebellar tract, in order to make predictions. Reafference signals and corollary discharges reach the comparator (inferior olive), which generates an error signal updating the plastic cerebellar microcircuits. Expected sensory outcomes are conveyed to the primary motor cortex via excitatory connections and to the inferior olive via inhibitory pathways.

Figure 11

Triphasic pattern of electromyographic (EMG) activities in a control subject (left) and in a cerebellar patient exhibiting hypermetria (right). In the control subject, the first agonist burst (AGO1) is followed by a burst in the antagonist muscle (ANTA), followed by a second burst in the agonist muscle (AGO2). In the cerebellar patient, three EMG deficits are observed: the rate of rise of EMG activities is depressed, the onset latency of the antagonist EMG activity is delayed and the 2 agonist bursts are not demarcated. FCR: flexor carpi radialis; ECR: extensor carpi radialis. EMG traces are full-wave rectified and averaged (n = 10 movements).

Figure 12

Inability to adapt to damping in cerebellar hypometria during fast reverse movements. Movement (top panels) and the associated EMG bursts in a control subject (left panels) and in an ataxic patient (right panels) for an aimed target of 0.3 rad are illustrated. Top panels: superimposition of fast reversal movements performed without damping (blue), with addition of 0.1 Nms/rad (black) or 0.2 Nms/rad (red). EMG bursts in the flexor carpi radialis (FCR) and the extensor carpi radialis (ECR) are calibrated with a reference to a maximal isotonic contraction (MIC) from 0 to 6 Nm (a.u.: arbitrary units). In each position panel, grey areas correspond to the 99% confidence interval of control values of movement amplitudes in the basal mechanical state (no addition of damping); dotted lines in black and red delineate the 99% confidence interval of control values during addition of 0.1 Nms/rad and 0.2 Nms/rad, respectively. In the patient, the first phase of movement (from the starting position to the target of 0.3 rad) remains accurate but the second phase (from the target of 0.3 rad to the return to the initial position) is hypometric. The hypometria is increased with addition of damping. Arrowheads located near the EMG traces indicate the onset of EMG bursts (blue: no damping, black: addition of 0.1 Nms/rad, red: addition of 0.2 Nms/rad). AGO1, AGO2 and ANTA1 correspond to the first burst in the FCR, the second burst in the FCR and the antagonist burst in the ECR, respectively. Arrowheads near AGO1, ANTA1, AGON2 and ANTA2 correspond to the onset of the first burst in the FCR, the first phase of the burst in the ECR, the second phase of the burst in the ECR, and the second burst in the FCR, respectively. AGO1 and ANTA2 are well demarcated in bottom left panel, unlike in the right bottom panel. Flex.: direction of flexion of the wrist; Ext.: wrist extension.

Figure 13

Long latency electromyographic (EMG) responses to stretches of the first dorsal interosseous muscle in a cerebellar patient (black line) and in a control subject (grey line). Latencies of averaged rectified EMG responses are normal, but the M3 response is increased in the cerebellar patient. Surface EMG rectified and averaged 200 times. Responses are calibrated in arbitrary units (a.u.).

Figure 14

Overview of the mechanisms of human cerebellar dysmetria.

Figure 15

Overview of the motor control strategy for limb movements. Cerebellum builds internal models and corrects motor commands, comparable to a system identification function. Basal ganglia ensures an optimal control of motion, facilitating motor commands. The parietal cortex integrates proprioceptive and visual outcomes, as well as sensory feedback, playing a role of state estimator. Premotor cortex and motor cortex transforms predictions into sets of motoneuronal discharges, encoding for force and direction of movement.

Figure 16

Representation of the sites of action of the cerebellum. Hill's muscle model and an operational model of the cerebellar circuitry are illustrated. Central and peripheral loops in the central nervous system are shown, with upper motoneuron (UMN)/lower motoneuron (LMN). IN indicates the pool of interneurons in the spinal cord. Cerebellar influences on spinal motoneurons are mainly indirect. DR corresponds to the dorsal root ganglia. The rectangle in the bottom represents Hill's muscle model (SE: series elastic component; NIP: neural input processor in parallel with a viscous component PE). Operational model of the cerebellar circuits: given inputs (IN) to a microzone (Micro) elicit an output (OUT) which depends on the whole complex of afferent information impinging upon the microzone. Adapted from Manzoni, 2007.