A Postural Tremor Highly Responsive to Transcranial Cerebello-Cerebral DCS in ARCA3.

BACKGROUND AND OBJECTIVES: Cerebellar ataxias are disabling disorders that impact the quality of life of patients. In many cases, an effective treatment is missing. Despite the increasing knowledge on the pathogenesis of cerebellar disorders including genetic aspects, there is currently a gap in the therapeutical management of cerebellar deficits. Cerebellar ataxia associated with ANO10 mutation (ARCA3) presents a disabling cerebellar syndrome. The aim of this study is to report a patient with a marked postural tremor responding to transcranial cerebello-cerebral direct current stimulation (tCCDCS). METHODS: We applied tCCDCS using anodal stimulation over the cerebellum with a return electrode on the contralateral motor cortex. We performed a clinical rating, accelerometry studies, and recordings of voluntary movements at baseline, after sham, and after active tCCDCS. RESULTS: A dramatic response of postural tremor was observed after tCCDCS, with a major drop of the power spectral density to 26.12% of basal values. DISCUSSION: The postural tremor of cerebellar ataxia associated with ANO10 mutation was highly responsive to tCCDCS in our patient. This case illustrates that tCCDCS is a novel therapeutic option in the treatment of cerebellar deficits and might represent a promising tool to reduce tremor in ARCA3.

The in vivo reduction of afferent facilitation induced by low frequency electrical stimulation of the motor cortex is antagonized by cathodal direct current stimulation of the cerebellum.

BACKGROUND: Low-frequency electrical stimulation to the motor cortex (LFSMC) depresses the excitability of motor circuits by long-term depression (LTD)-like effects. The interactions between LFSMC and cathodal direct current stimulation (cDCS) over the cerebellum are unknown. METHODS: We assessed the corticomotor responses and the afferent facilitation of corticomotor responses during a conditioning paradigm in anaesthetized rats. We applied LFSMC at a frequency of 1 Hz and a combination of LFSMC with cDCS. RESULTS: LFSMC significantly depressed both the corticomotor responses and the afferent facilitation of corticomotor responses. Simultaneous application of cDCS over the cerebellum antagonized the depression of corticomotor responses and cancelled the depression of the afferent facilitation. CONCLUSION: Our results demonstrate that cDCS of the cerebellum is a potent modulator the inhibition of the motor circuits induced by LFSMC applied in vivo. These results expand our understanding of the effects of cerebellar DCS on motor commands and open novel applications for a cerebellar remote control of LFSMC-induced neuroplasticity. We suggest that the cerebellum acts as a neuronal machine supervising not only long-term potentiation (LTP)-like effects, but also LTD-like effects in the motor cortex, two mechanisms which underlie cerebello-cerebral interactions and the cerebellar control of remote plasticity. Implications for clinical ataxiology are discussed.

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.

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 contributions of the cerebellum in sensorimotor control: what are the prevailing opinions which will guide forthcoming studies?

Although considerable progress has been made in developing models of cerebellar function in sensorimotor control, the exact nature of the basic operations performed by the cerebellum remain elusive. Several major theories have emerged these last decades. According to the hypothesis of Marr and Albus, the climbing fiber input carries an error signal weakening the strength of a subset of parallel fibers/Purkinje neurons synapses in the cerebellar cortex. Cerebellar circuits would gain the control of movement through trial and error. The hypothesis of internal models emulating movements is currently highly cited. There is a general agreement that (1) the central nervous system has to cope with an intrinsic time delay of sensory feedback related to motor activities and (2) estimations of future motor states are essential to perform fast and accurate movements. According to this second theory, cerebellar dysmetria, one of the cardinal cerebellar deficits, would result from a distorted predictive control. A third popular theory relates to the inverse models that would be stored in the cerebellum. Acquisition of a motor act would require forward models, and the acquisition process itself would generate an inverse model to allow an unconscious coordinated movement. Recently, an international panel of experts from various disciplines discussed the prevailing opinions in a consensus statement and tried to extract their clinical relevance in terms of pathogenesis of the clinical symptoms. Although a consensus is still not reached, the prevailing opinions provide a sound framework to conduct novel studies and try to discover the secrets of cerebellar circuits.

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.

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. (C) ICF was depressed in the right motor cortex, but increased similarly on both sides following LFS/HFS. These results (1) confirm the increased inhibition in the motor cortex contralaterally to the hemicerebellar ablation, (2) demonstrate for the first time that the cerebellum is necessary for tuning amplitudes of corticomotor responses following a peripheral nerve stimulation, (3) show that the application of LFS or HFS does not cancel the defect of excitability in the motor cortex for short ISIs, and (4) suggest that for longer ISIs, HFS could have interesting properties for the modulation of afferent inhibition in case of extensive cerebellar lesion. Our study underlines that cerebellar ablation impacts on the efficacy of combined peripheral-motor cortex stimulation in an ISI-dependent manner.

Reinstating the ability of the motor cortex to modulate cutaneomuscular reflexes in hemicerebellectomized rats.

The pathways passing through the cerebellum calibrate cutaneomuscular responses. Indeed, the enhancement of cutaneomuscular responses associated with subthreshold high-frequency trains of stimulation applied on motor cortex following a period of peripheral repetitive stimulation (PRS) is prevented by hemicerebellectomy. We analysed the effects of low-frequency repetitive stimulation of motor cortex (LFRSM1) on interhemispheric inhibition (IHI) and on the modulation of cutaneomuscular reflexes in rats with left hemicerebellar ablation. IHI was assessed by paired-pulse method with a conditioning stimulus (CS) to M1 followed by a test stimulus (TS) to the opposite M1. LFRSM1 reduced IHI. Combination of LFRSM1 with PRS increased significantly the magnitudes of cutaneomuscular responses evoked ipsilaterally to the hemicerebellar ablation. The increase of the intensity of cutaneomuscular responses was correlated with the reduction of IHI. Excitability of anterior horn motoneurons pool, assessed by F-wave, remained unchanged. Conjunction of LFRSM1 with PRS can be used to restore the ability of the motor cortex to modulate the intensity of cutaneomuscular responses in case of extensive unilateral cerebellar lesion. This study underlines for the first time the potential role of callosal pathways in the deficits of corticomotor tuning of cutaneomuscular responses contralaterally to acute extensive cerebellar lesion.

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.

[Metastasis of a lumbosacral ependymoma with very long disease-free survival: a case report and review of the literature]. / Métastase d'un épendymome lombosacré avec très long intervalle libre: cas clinique et revue de la littérature.

Ependymoma is rare glial tumour of the central nervous system and is considered to be low-grade. The lumbosacral location of spinal ependymoma is the most common. Prognosis of ependymomas is dependent on tumour location, histological subtype and differentiation, extent of the tumour and of the completeness of the surgical resection. One of the characteristics of this kind of tumour is to present the possibility of a seeding of the entire cerebrospinal axis, by the way of cerebrospinal liquid. We describe the case of a young male patient operated by incomplete resection of a lumbar ependymoma. Six months later, the patient's symptoms reappeared and an external radiotherapy at curative doses and chemotherapy were delivered. Evolution of the remaining tumour was diagnosed 6 years after at the primary site and operated by large incomplete resection. A second session of radiotherapy was therefore administered. Twenty-four years after this episode, cervical pain and gait troubles appear. Complete imaging study concluded to a cervical extramedullary intradural tumour and to the persistence of the primary lumbosacral tumour. Macroscopical complete resection of the cervical tumour was performed and pathological findings concluded to a metastasis of his lumbar ependymoma. External radiotherapy was delivered on this site with a total dose of 50 Gy. Eight years after this episode, the patient is alive without evidence of distant disease. The primary lumbosacral ependymoma is stable. Ependymomas are often recurrent at the primary site, but can seed on the entire cerebrospinal axis. Awareness of such aberrant tumoral behaviour, even after such a long disease free interval, may warrant more careful follow-up of patients with this diagnosis.

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.

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 micromol/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 muV. 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.

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.