Nordeyn Oulad Ben Taib

Consensus paper: roles of the cerebellum in motor control--the diversity of ideas on cerebellar involvement in movement.

Considerable progress has been made in developing models of cerebellar function in sensorimotor control, as well as in identifying key problems that are the focus of current investigation. In this consensus paper, we discuss the literature on the role of the cerebellar circuitry in motor control, bringing together a range of different viewpoints. The following topics are covered: oculomotor control, classical conditioning (evidence in animals and in humans), cerebellar control of motor speech, control of grip forces, control of voluntary limb movements, timing, sensorimotor synchronization, control of corticomotor excitability, control of movement-related sensory data acquisition, cerebro-cerebellar interaction in visuokinesthetic perception of hand movement, functional neuroimaging studies, and magnetoencephalographic mapping of cortico-cerebellar dynamics. While the field has yet to reach a consensus on the precise role played by the cerebellum in movement control, the literature has witnessed the emergence of broad proposals that address cerebellar function at multiple levels of analysis. This paper highlights the diversity of current opinion, providing a framework for debate and discussion on the role of this quintessential vertebrate structure.

Modulation of motor cortex excitability by sustained peripheral stimulation: The interaction between the motor cortex and the cerebellum

The excitability of cortical neurons in the motor cortex is determined by their membrane potential and by the level of intracortical inhibition. The excitability of the motor cortex as a whole is a function of single cell excitability, synaptic strength, and the balance between excitatory cells and inhibitory cells. It is now established that a sustained period of somatosensory stimulation increases the excitability of motor cortex areas controlling muscles in those body parts that received the stimulation prior to excitability testing. So far, it has been supposed that the sensorimotor cortex was the anatomical substrate of these excitability changes, which could represent an early change in cortical network function before structural plasticity occurs. Recent experimental studies highlight that the cerebellum, especially the interpositus nucleus, plays a key role in the adaptation of the motor cortex to repeated trains of stimulation. Interpositus neurons, which receive inputs from both sensorimotor cortex and the spinal cord, are involved in somesthetic reflex behaviors and assist the cerebral cortex in transforming sensory signals to motor-oriented commands by acting via the cerebello-thalamo-cortical projections. Moreover, climbing fibers originating in the inferior olivary complex and innervating the nucleus interpositus mediate highly integrated sensorimotor information derived from spinal modules. It appears that the interpositus nucleus is a main subcortical modulator of the excitability changes occurring in the motor cortex, which may be a substrate of early plasticity effective in motor learning and recovery from lesion.

Marked reduction of cerebellar deficits in upper limbs following transcranial cerebello-cerebral DC stimulation: tremor reduction and re-programming of the timing of antagonist commands.

Cerebellar ataxias represent a very heterogeneous group of disabling disorders for which we lack effective symptomatic therapies in most cases. There is currently an intense interest in the use of non-invasive transcranial DC stimulation (tDCS) to modulate the activity of the cerebellum in ataxic disorders. We performed a detailed laboratory assessment of the effects of transcranial cerebello-cerebral DC stimulation (tCCDCS, including a sham procedure) on upper limb tremor and dysmetria in 2 patients presenting a dominant spinocerebellar ataxia (SCA) type 2, one of the most common SCAs encountered during practice. Both patients had a very similar triplet expansion size in the ATXN2 gene (respectively, 39 and 40 triplets). tCCDCS reduced both postural tremor and action tremor, as confirmed by spectral analysis. Quadratical PSD (power spectral density) of postural tremor dropped to 38.63 and 41.42% of baseline values in patient 1 and 2, respectively. The integral of the subband 4–20 Hz dropped to 46.9 and 62.3% of baseline values, respectively. Remarkably, tCCDCS canceled hypermetria and reduced dramatically the onset latency of the antagonist EMG activity associated with fast goal-directed movements toward 3 aimed targets (0.2, 0.3, and 0.4 rad). Following tCCDCS, the latency dropped from 108–98 to 63–57 ms in patient 1, and from 74–87 to 41–46 ms in patient 2 (mean control values ± SD: 36 ± 8 to 45 ± 11 ms), corresponding to a major drop of z scores for the 2 patients from 7.12 ± 0.69 to 1.28 ± 1.27 (sham procedure: 6.79 ± 0.71). This is the first demonstration that tCCDCS improves upper limb tremor and hypermetria in SCA type 2. In particular, this is the first report of a favorable effect on the onset latency of the antagonist EMG activity, a neurophysiological marker of the defect in programming of timing of motor commands. Our results indicate that tCCDCS should be considered in the symptomatic management of upper limb motor deficits in cerebellar ataxias. Future studies addressing a tDCS-based neuromodulation to improve motor control of upper limbs are required (a) in a large group of cerebellar disorders, and (b) in different subgroups of ataxic patients. The anatomical location of the cerebellum below the skull is particularly well suited for such studies.

Modulation of excitability as an early change leading to structural adaptation in the motor cortex.

The excitability of the motor cortex is a function of single cell excitability, synaptic strength, and the balance between excitatory cells and inhibitory cells. Sustained periods of sensory stimulation enhance the excitability in the motor cortex. This adaptation, which represents an early change in cortical network function effective in motor learning and recovery from a motor deficit, is followed by longer‐lasting changes, such as modifications in cortical somatotopy, and by structural plasticity. Interventions aiming at increasing excitability also positively affect learning processes. Recent studies highlight that the cerebellum, especially the interpositus nucleus, plays a key function in the adaptation of the motor cortex to repeated trains of peripheral stimulation. Interpositus neurons, which receive inputs from the sensorimotor cortex and the spinal cord, are involved in somesthetic reflex behaviors and assist the cerebral cortex in transforming sensory signals to motor‐oriented commands by acting via the cerebello‐thalamo‐cortical projections. Moreover, climbing fibers originating in the inferior olivary complex and innervating the nucleus interpositus mediate highly integrated sensorimotor information derived from spinal modules. The intermediate cerebellum allows the motor cortex to tune the gain of polysynaptic responses originating from the spinal cord after repetitive trains of peripheral stimulation, allowing an online calibration of cutaneo‐muscular responses.

Trains of Epidural DC Stimulation of the Cerebellum Tune Corticomotor Excitability

We assessed the effects of anodal/cathodal direct current stimulation (DCS) applied epidurally over the cerebellum. We studied the excitability of both the motor cortex and the anterior horn of the spinal cord in adult rats under continuous anesthesia. We also investigated the effects on the spatial representation of a couple of agonist/antagonist muscles on primary motor cortex. Moreover, we evaluated the effects on the afferent inhibition in a paradigm of conditioned corticomotor responses. Anodal DCS of the cerebellum (1) decreased the excitability of the motor cortex, (2) reduced the excitability of F waves, as shown by the decrease of both mean F/mean M ratios and persistence of F waves, (3) exerted a “smoothing effect” on corticomotor maps, reshaping the representation of muscles on the motor cortex, and (4) enhanced the afferent inhibition of conditioned motor evoked responses. Cathodal DCS of the cerebellum exerted partially reverse effects. DCS of the cerebellum modulates the excitability of both motor cortex and spinal cord at the level of the anterior horn. This is the first demonstration that cerebellar DCS tunes the shape of corticomotor maps. Our findings provide a novel mechanism by which DCS of the cerebellum exerts a remote neuromodulatory effect upon motor cortex.

The cerebellum modulates rodent cortical motor output after repetitive somatosensory stimulation

OBJECTIVE:To analyze the possible role of the cerebellum in the modulation of cortical motor output associated with repetitive electrical stimulation of the sciatic nerve in the rat. METHODS:A sustained somatosensory stimulation induces an increase in the intensity of the response of the rodent motor cortex. Wistar rats were anesthetized for surgical preparation using a continuous infusion of chloral hydrate. We analyzed the response evoked by electrical stimulation of the right motor cortex before (basal condition) and after peripheral electrical stimulation of the left sciatic nerve in rats with no cerebellar intervention (n = 6), and in control rats with Ringer’s infusion via a microdialysis probe (n = 8) implanted in the left cerebellar nuclei. In addition, we investigated the effects of 1) the administration of ethanol (20 mmol/L) in the left cerebellar nuclei (n = 5); 2) the administration of tetrodotoxin (10 &mgr;mol/L), a sodium channel blocker, in the left cerebellar nuclei (n = 5); 3) electrical stimulation by deep cerebellar stimulation (frequency 100 Hz) on the left side (n = 5); or 4) electrical stimulation of the cerebellar nuclei on the right side (100 Hz; n = 6). For peripheral stimulation, all of the animals received 1 hour of electrical stimulation. Trains of stimulation consisted of five stimuli (duration of 1 stimulus, 1 ms) at a rate of 10 Hz. During stimulation of the motor cortex, peak-to-peak amplitudes in responses of the left calf muscle were analyzed. Motor threshold was defined as the lowest intensity eliciting at least 5 of 10 evoked responses with an amplitude greater than 20 &mgr;V. The intensity used was 130% of the motor threshold. RESULTS:In the basal condition (before repetitive stimulation), amplitudes of motor responses were similar in the six groups of rats (P = 0.40). In rats without cerebellar intervention, peripheral electrical stimulation was associated with an increase of motor response to 147.4 ± 8.5% of baseline (P < 0.001). In rats with Ringer’s infusion, the motor response increased to 141.6 ± 7.9% of baseline (P < 0.001). The administration of ethanol in the cerebellum prevented the enhancement of the response ipsilaterally. The mean ± standard deviation (SD) of motor responses was 105.7 ± 6.2% of baseline measurements after stimulation of the sciatic nerve (P = 0.36). The same observation was made after the infusion of tetrodotoxin (mean ± SD of motor responses: 107.1 ± 7.4% after peripheral stimulation [P = 0.19] and after electrical stimulation of the cerebellum on the left side [mean ± SD of motor responses, 104.3 ± 8.5% after peripheral stimulation, P = 0.40]). However, electrical stimulation of cerebellar nuclei on the right side did not impair the modulation of cortical motor output by sciatic nerve stimulation (mean ± SD of motor responses, 148.4 ± 5.8% after peripheral stimulation, P < 0.001). CONCLUSION:Until now, the increase of motor output after peripheral nerve stimulation has been considered as a plasticity directly and solely dependent on cortical structures. We demonstrate that the cerebellum plays a key role in this form of neural plasticity.

Effects of trains of high-frequency stimulation of the premotor/supplementary motor area on conditioned corticomotor responses in hemicerebellectomized rats.

We studied the effects of low- and high-frequency premotor electrical stimulations on conditioned corticomotor responses, intra-cortical facilitation (ICF) and spinal excitability in hemicerebellectomized rats (left side). Trains of stimulation were applied in prefrontal region rFr2 (the equivalent of the premotor/supplementary motor area in primates) at a rate of 1 Hz (low-frequency stimulation LFS) or 20 Hz (high-frequency stimulation HFS). Test stimuli on the motor cortex were preceded by a conditioning stimulus in contralateral sciatic nerve (two inter-stimulus intervals ISIs were studied: 5 ms or 45 ms). (A) At ISI-5, conditioning increased amplitudes of MEPs (motor evoked potentials) in the left motor cortex. This afferent facilitation was enhanced if preceded by trains of stimuli administered over the ipsilateral rFr2 area, and HFS had higher effects than LFS. The facilitation was lower for the right motor cortex, for both LFS and HFS. (B) At ISI-45, conditioned motor evoked responses were depressed as compared to unconditioned responses in the left motor cortex (afferent inhibition). Following LFS, the degree of inhibition was unchanged while it increased with HFS. At baseline, inhibition was enhanced in the right motor cortex. Interestingly, the afferent inhibition decreased significantly following HFS

Hemicerebellectomy impairs the modulation of cutaneomuscular reflexes by the motor cortex following repetitive somatosensory stimulation.

We examined the cutaneomuscular reflex of the plantaris muscle of rats in response to cutaneous stimulation in isolation and in conjunction with subthreshold high-frequency trains of stimuli applied on the motor cortex, prior to and following repetitive peripheral stimulation. The cutaneomuscular reflex was also investigated under the same paradigm following hemicerebellectomy. The enhancement of cutaneomuscular responses associated with subthreshold high-frequency trains of stimulation following repetitive peripheral stimulation was prevented by hemicerebellectomy. Our results suggest that the pathways passing through the cerebellum are involved in the calibration of cutaneomuscular responses.

Cerebellar Nuclei: Key Roles for Strategically Located Structures

With the exception of vestibular information, cerebellar nuclei represent the unique source of output of the cerebellar circuitry. The fastigial (FN), globose/emboliform (interpositus, IN), and dentate (DN) nuclei receive inhibitory GABAergic signals from Purkinje neurons and send back fibers to the cerebellar cortex. The numerous GABAA inhibitory synapses between cerebellar cortex and cerebellar nuclei allow responses to high-frequency Purkinje cell firing [1]. Cerebellar nuclei receive excitatory collaterals of mossy fibers and climbing fibers, especially via AMPA and NMDA receptors [2]. A subset of small neurons in cerebellar nuclei project to the inferior olivary complex, providing a feedback to the inferior olive. Cerebellar nuclei thus integrate the converging excitatory and inhibitory signals to provide the final output of the cerebellar circuits. Each cerebellar nucleus has a separate somatotopic representation of the body [3]. The projections to different cerebral cortical areas originate from distinct areas of cerebellar nuclei. In particular, the DN is spatially divided into a motor and nonmotor zone, with a closed loop from the nucleus to the cerebral cortex and back to the nucleus. Cerebellar nuclei control differentially the medial and lateral motor systems and their functions [4]. The vestibular and FN are concerned with the control of eye movements, control of head orientation, stance, and gait. FN can be functionally divided into rostral and caudal components [4, 5]. The rostral portion is involved in the control of somatic musculature, head orientation, and eye-gaze shifts [4]. The caudal FN plays key roles in saccade generation and smooth pursuit [6]. The IN is particularly active during the modulation of various reflexes and sensory feedback [7]. The eyeblink responses are typically associated with a modulation of activity in behaving animals [8]. The intermediate cortex and the IN fire in relation to the antagonist muscle group [9, 10], in agreement with a role in damping the limb oscillations and compensation of errors [11]. The IN participates in the excitability of the stretch reflexes [12]. The DN is especially concerned with voluntary movements of the extremities, including reaching and grasping. Dentate neurons preferentially fire at the onset of movement triggered by mental associations [4]. An influential theory is that cerebellar nuclei constitute temporal pattern generators that can contribute to the precise temporal control of motor or cognitive events [13, 14]. The plasticity of Purkinje neurons–cerebellar nuclei synapses is based upon synaptically driven changes in excitability and LTP/LTD [15–17]. In conjunction with the LTP/LTD in cerebellar cortex and the adaptations occurring in mossy/ climbing fibers, such plasticity allows for reshaping of patterns of activities in cerebellar nuclei. On the basis of GABA decarboxylase isoform 67 (GAD67) expression and electrophysiological properties, three types of cerebellar nuclei neurons have been described [18]: the large non-GABAergic neurons (“GADnL”; putatively corresponding to the glutamatergic projection neurons) and two classes of smaller neurons, one M. Manto :N. Oulad Ben Taib Service de Neurologie et Neurochirurgie, ULB Erasme, Brussels, Belgium

Interaction between repetitive stimulation of the sciatic nerve and functional ablation of cerebellar nucleus interpositus in the rat

It is established that cerebellar nuclei exert a significant effect on the excitability of spinal neurons. However, their output is heterogeneous. Conditioning trains of dentate nucleus stimuli are known to modify the post-synaptic potentials evoked in motoneurons by stimulation of group Ia and Ib afferents in appropriate peripheral nerves. The role of the interpositus nucleus in the modulation of the excitability of rat spinal cord remains unclear. We investigated the interactions between tetrodotoxin (TTX)-induced inactivation of the interpositus cerebellar nuclei and repetitive electrical stimulation of the ipsilateral sciatic nerve (proximal segment) in the anesthetized rat. TTX (10 microM) was administered in cerebellar nuclei by the technique of microdialysis (coordinates of the extremity of the guide related to bregma: AP: -11.6, L: +2.3, V: -4.6). Peripheral stimulation consisted of trains of electric stimuli at a rate of 10 Hz, which were repeated every second during 1 hour. Stimulus intensity was adjusted to produce constant somatosensory evoked potentials. H-reflex, F-wave and M responses of the plantaris muscles were analysed ipsilaterally. H-reflex recruitment curve, Hmax/Mmax ratios, F-wave persistence and mean F/mean M ratios were studied. Functional blockade of cerebellar interpositus nucleus reduced the slope of H-reflex recruitment curve without affecting the Hmax/Mmax ratio, and depressed both F-waves persistence and mean F/mean M ratios. Concomitant repetitive stimulation of the sciatic nerve counteracted the depression of the H-reflex recruitment curve, without interacting with F-waves depression. Our results (1) show that TTX-sensitive sodium channels in cerebellar nucleus interpositus modulate the H-reflex recruitment, and (2) reveal an interaction between TTX-sensitive sodium channels in cerebellar nuclei and afferent repetitive activity not described so far.