Cerebellar Transcranial Direct Current Stimulation Reconfigures Brain Networks Involved in Motor Execution and Mental Imagery.

Transcranial direct current stimulation (tDCS) is growingly applied to the cerebellum to modulate the activity of cerebellar circuitry, affecting both motor and cognitive performances in a polarity-specific manner. The remote effects of tDCS are mediated in particular via the dentato-thalamo-cortical pathway. We showed recently that tDCS of the cerebellum exerts dynamic effects on resting state networks. We tested the neural hypothesis that tDCS reconfigurates brain networks involved in motor execution (ME) and motor mental imagery (MMI). We combined tDCS applied over the right cerebellum and fMRI to investigate tDCS-induced reconfiguration of ME- and MMI-related networks using a randomized, sham-controlled design in 21 right-handed healthy volunteers. Subjects were instructed to draw circles at comfortable speed and to imagine drawing circles with their right hand. fMRI data were recorded after real anodal stimulation (1.5 mA, 20 min) or sham tDCS. Real tDCS compared with SHAM specifically reconfigurated the functional links between the main intrinsic connected networks, especially the central executive network, in relation with lobule VII, and the salience network. The right cerebellum mainly influenced prefrontal and anterior cingulate areas in both tasks, and improved the overt motor performance. During MMI, the cerebellum also modulated the default-mode network and associative visual areas. These results demonstrate that tDCS of the cerebellum represents a novel tool to modulate cognitive brain networks controlling motor execution and mental imagery, tuning the activity of remote cortical regions. This approach opens novel doors for the non-invasive neuromodulation of disorders involving cerebello-thalamo-cortical paths.

New Horizons on Non-invasive Brain Stimulation of the Social and Affective Cerebellum.

The cerebellum is increasingly attracting scientists interested in basic and clinical research of neuromodulation. Here, we review available studies that used either transcranial magnetic stimulation (TMS) or transcranial direct current stimulation (tDCS) to examine the role of the posterior cerebellum in different aspects of social and affective cognition, from mood regulation to emotion discrimination, and from the ability to identify biological motion to higher-level social inferences (mentalizing). We discuss how at the functional level the role of the posterior cerebellum in these different processes may be explained by a generic prediction mechanism and how the posterior cerebellum may exert this function within different cortico-cerebellar and cerebellar limbic networks involved in social cognition. Furthermore, we suggest to deepen our understanding of the cerebro-cerebellar circuits involved in different aspects of social cognition by employing promising stimulation approaches that have so far been primarily used to study cortical functions and networks, such as paired-pulse TMS, frequency-tuned stimulation, state-dependent protocols, and chronometric TMS. The ability to modulate cerebro-cerebellar connectivity opens up possible clinical applications for improving impairments in social and affective skills associated with cerebellar abnormalities.

Cerebellar transcranial direct current stimulation reconfigurates static and dynamic functional connectivity of the resting-state networks.

BACKGROUND: Transcranial direct current stimulation (tDCS) of the cerebellum dynamically modulates cerebello-thalamo-cortical excitability in a polarity-specific manner during motor, visuo- motor and cognitive tasks. It remains to be established whether tDCS of the cerebellum impact also on resting-state intrinsically connected networks (ICNs). Such impact would open novel research and therapeutical doors for the neuromodulation of ICNs in human. METHOD: We combined tDCS applied over the right cerebellum and fMRI to investigate tDCS- induced resting-state intrinsic functional reconfiguration, using a randomized, sham-controlled design. fMRI data were recorded both before and after real anodal stimulation (2 mA, 20 min) or sham tDCS in 12 right-handed healthy volunteers. We resorted to a region-of-interest static correlational analysis and to a sliding window analysis to assess temporal variations in resting state FC between the cerebellar lobule VII and nodes of the main ICNs. RESULTS: After real tDCS and compared with sham tDCS, functional changes were observed between the cerebellum and ICNs. Static FC showed enhanced or decreased correlation between cerebellum and brain areas belonging to visual, default-mode (DMN), sensorimotor and salience networks (SN) (p-corrected < 0.05). The temporal variability (TV) of BOLD signal was significantly modified after tDCS displaying in particular a lesser TV between the whole lobule VII and DMN and central executive network and a greater TV between crus 2 and SN. Static and dynamic FC was also modified between cerebellar lobuli. CONCLUSION: These results demonstrate short- and long-range static and majorly dynamic effects of tDCS stimulation of the cerebellum affecting distinct resting-state ICNs, as well as intracerebellar functional connectivity, so that tDCS of the cerebellum appears as a non-invasive tool reconfigurating the dynamics of ICNs.

Consensus Paper. Cerebellar Reserve: From Cerebellar Physiology to Cerebellar Disorders.

Cerebellar reserve refers to the capacity of the cerebellum to compensate for tissue damage or loss of function resulting from many different etiologies. When the inciting event produces acute focal damage (e.g., stroke, trauma), impaired cerebellar function may be compensated for by other cerebellar areas or by extracerebellar structures (i.e., structural cerebellar reserve). In contrast, when pathological changes compromise cerebellar neuronal integrity gradually leading to cell death (e.g., metabolic and immune-mediated cerebellar ataxias, neurodegenerative ataxias), it is possible that the affected area itself can compensate for the slowly evolving cerebellar lesion (i.e., functional cerebellar reserve). Here, we examine cerebellar reserve from the perspective of the three cornerstones of clinical ataxiology: control of ocular movements, coordination of voluntary axial and appendicular movements, and cognitive functions. Current evidence indicates that cerebellar reserve is potentiated by environmental enrichment through the mechanisms of autophagy and synaptogenesis, suggesting that cerebellar reserve is not rigid or fixed, but exhibits plasticity potentiated by experience. These conclusions have therapeutic implications. During the period when cerebellar reserve is preserved, treatments should be directed at stopping disease progression and/or limiting the pathological process. Simultaneously, cerebellar reserve may be potentiated using multiple approaches. Potentiation of cerebellar reserve may lead to compensation and restoration of function in the setting of cerebellar diseases, and also in disorders primarily of the cerebral hemispheres by enhancing cerebellar mechanisms of action. It therefore appears that cerebellar reserve, and the underlying plasticity of cerebellar microcircuitry that enables it, may be of critical neurobiological importance to a wide range of neurological/neuropsychiatric conditions.

Apraxia of speech and cerebellar mutism syndrome: a case report.

BACKGROUND: Cerebellar mutism syndrome (CMS) or posterior fossa syndrome (PFS) consists of a constellation of neuropsychiatric, neuropsychological and neurogenic speech and language deficits. It is most commonly observed in children after posterior fossa tumor surgery. The most prominent feature of CMS is mutism, which generally starts after a few days after the operation, has a limited duration and is typically followed by motor speech deficits. However, the core speech disorder subserving CMS is still unclear. CASE PRESENTATION: This study investigates the speech and language symptoms following posterior fossa medulloblastoma surgery in a 12-year-old right-handed boy. An extensive battery of formal speech (DIAS = Diagnostic Instrument Apraxia of Speech) and language tests were administered during a follow-up of 6 weeks after surgery. Although the neurological and neuropsychological (affective, cognitive) symptoms of this patient are consistent with Schmahmann's syndrome, the speech and language symptoms were markedly different from what is typically described in the literature. In-depth analyses of speech production revealed features consistent with a diagnosis of apraxia of speech (AoS) while ataxic dysarthria was completely absent. In addition, language assessments showed genuine aphasic deficits as reflected by distorted language production and perception, wordfinding difficulties, grammatical disturbances and verbal fluency deficits. CONCLUSION: To the best of our knowledge this case might be the first example that clearly demonstrates that a higher level motor planning disorder (apraxia) may be the origin of disrupted speech in CMS. In addition, identification of non-motor linguistic disturbances during follow-up add to the view that the cerebellum not only plays a crucial role in the planning and execution of speech but also in linguistic processing. Whether the cerebellum has a direct or indirect role in motor speech planning needs to be further investigated.

Trains of electrical stimulation of the trapezius muscles redistribute the frequencies of body oscillations during stance.

We investigated the postural effects of trains of electrical stimulation (TES) applied unilaterally or bilaterally on the trapezius muscle in 20 healthy subjects (mean age: 23.1 ± 1.33 years; F/M: 8/12). The anterior-posterior (AP) displacements (AP axis), medio-lateral displacements (ML axis) and total travelled distances (TTW) of the centre of pressure (COP) remained unchanged with TES. However, detailed spectral analysis of COP oscillations revealed a marked decrease of the magnitudes of peak power spectral density (peak PSD) following application of TES. Peak PSD was highly correlated with the intensity of stimulation (P < 0.001 both the AP and ML axes). For the AP axis, the integrals of the sub-bands 0-0.4, 0.4-1.5, 1.5-3 Hz were significantly decreased (P < 0.001), the integrals of the sub-bands 3-5 and 5-8 Hz were not significantly affected (P>0.30) and the integrals of the sub-band 8-10 Hz were significantly increased (P < 0.001). The ratios of the integrals of sub-bands 8-10 Hz/0-3 Hz were markedly enhanced with bilateral TES (P < 0.001). For the ML axis, the effects were striking (P < 0.001) for the sub-bands 0-0.4, 0.4-1.5 and 8-10 Hz. For both the AP and ML axes, a significant inverse linear relationship was found between the intensity of TES and the average speed of COP. We show that TES applied over the trapezius muscles exerts significant and so far unrecognised effects upon oscillations of the COP, decreasing low-frequency oscillations and enhancing high-frequency oscillations. Our data unravel a novel property of the trapezius muscles upon postural control. We suggest that this muscle plays a role of a distributor of low-frequency versus high-frequency sub-bands of frequency during stance. Previous studies have shown that patients with supra-tentorial stroke show an increased peak PSD in low frequencies of body oscillations. Therefore, our findings provide a rationale to assess neurostimulation of the trapezius muscle in the rehabilitation of postural deficits in supra-tentorial stroke.

Reorganization of large-scale cognitive networks during automation of imagination of a complex sequential movement.

We investigated the functional reconfiguration of the cerebral networks involved in imagination of sequential movements of the left foot, both performed at regular and fast speed after mental imagery training. Thirty-five volunteers were scanned with a 3T MRI while they imagined a sequence of ankle movements (dorsiflexion, plantar flexion, varus and valgus) before and after mental practice. Subjects were distributed in two groups: the first group executed regular movements whereas the second group made fast movements. We applied the general linear model (GLM) and model-free, exploratory tensorial independent component analytic (TICA) approaches to identify plastic post-training effects on brain activation. GLM showed that post-training imagination of movement was accompanied by a dual effect: a specific recruitment of a medial prefronto-cingulo-parietal circuit reminiscent of the default-mode network, with the left putamen, and a decreased activity of a lateral fronto-parietal network. Training-related subcortical changes only consisted in an increased activity in the left striatum. Unexpectedly, no difference was observed in the cerebellum. TICA also revealed involvement of the left executive network, and of the dorsal control executive network but no significant differences were found between pre- and post-training phases. Therefore, repetitive motor mental imagery induced specific putamen (motor rehearsal) recruitment that one previously observed during learning of overt movements, and, simultaneously, a specific shift of activity from the dorsolateral prefrontal cortex (attention, working memory) to the medial posterior parietal and cingulate cortices (mental imagery and memory rehearsal). Our data complement and confirm the notion that differential and coupled recruitment of cognitive networks can constitute a neural marker of training effects.

Targeting the red nucleus for cerebellar tremor.

Deep brain stimulation of the thalamus (and especially the ventral intermediate nucleus) does not significantly improve a drug-resistant, disabling cerebellar tremor. The dentato-rubro-olivary tract (Guillain-Mollaret triangle, including the red nucleus) is a subcortical loop that is critically involved in tremor genesis. We report the case of a 48-year-old female patient presenting with generalized cerebellar tremor caused by alcohol-related cerebellar degeneration. Resistance to pharmacological treatment and the severity of the symptoms prompted us to investigate the effects of bilateral deep brain stimulation of the red nucleus. Intra-operative microrecordings of the red nucleus revealed intense, irregular, tonic background activity but no rhythmic components that were synchronous with upper limb tremor. The postural component of the cerebellar tremor disappeared during insertion of the macro-electrodes and for a few minutes after stimulation, with no changes in the intentional (kinetic) component. Stimulation per se did not reduce postural or intentional tremor and was associated with dysautonomic symptoms (the voltage threshold for which was inversed related to the stimulation frequency). Our observations suggest that the red nucleus is (1) an important centre for the genesis of cerebellar tremor and thus (2) a possible target for drug-refractory tremor. Future research must determine how neuromodulation of the red nucleus can best be implemented in patients with cerebellar degeneration.

Non-invasive cerebellar stimulation--a consensus paper.

The field of neurostimulation of the cerebellum either with transcranial magnetic stimulation (TMS; single pulse or repetitive (rTMS)) or transcranial direct current stimulation (tDCS; anodal or cathodal) is gaining popularity in the scientific community, in particular because these stimulation techniques are non-invasive and provide novel information on cerebellar functions. There is a consensus amongst the panel of experts that both TMS and tDCS can effectively influence cerebellar functions, not only in the motor domain, with effects on visually guided tracking tasks, motor surround inhibition, motor adaptation and learning, but also for the cognitive and affective operations handled by the cerebro-cerebellar circuits. Verbal working memory, semantic associations and predictive language processing are amongst these operations. Both TMS and tDCS modulate the connectivity between the cerebellum and the primary motor cortex, tuning cerebellar excitability. Cerebellar TMS is an effective and valuable method to evaluate the cerebello-thalamo-cortical loop functions and for the study of the pathophysiology of ataxia. In most circumstances, DCS induces a polarity-dependent site-specific modulation of cerebellar activity. Paired associative stimulation of the cerebello-dentato-thalamo-M1 pathway can induce bidirectional long-term spike-timing-dependent plasticity-like changes of corticospinal excitability. However, the panel of experts considers that several important issues still remain unresolved and require further research. In particular, the role of TMS in promoting cerebellar plasticity is not established. Moreover, the exact positioning of electrode stimulation and the duration of the after effects of tDCS remain unclear. Future studies are required to better define how DCS over particular regions of the cerebellum affects individual cerebellar symptoms, given the topographical organization of cerebellar symptoms. The long-term neural consequences of non-invasive cerebellar modulation are also unclear. Although there is an agreement that the clinical applications in cerebellar disorders are likely numerous, it is emphasized that rigorous large-scale clinical trials are missing. Further studies should be encouraged to better clarify the role of using non-invasive neurostimulation techniques over the cerebellum in motor, cognitive and psychiatric rehabilitation strategies.

Brain areas involved in the control of speed during a motor sequence of the foot: real movement versus mental imagery.

We investigated the cerebral networks involved in execution and mental imagery of sequential movements of the left foot, both performed at slow and fast speed. Twelve volunteers were scanned with a 3T MRI during execution and imagination of a sequence of ankle movements. Overt movement execution and motor imagery shared a common network including the premotor, parietal and cingulate cortices, the striatum and the cerebellum. Motor imagery recruited specifically the prefrontal cortex, whereas motor execution recruited specifically the sensorimotor cortex. We also found that slow movements specifically recruited frontopolar and right dorsomedian prefrontal areas bilaterally, during both execution and mental imagery, whereas fast movements strongly activated the sensorimotor cerebral cortex. Finally, we noted that anterior vermis, lobules VI/VII and VIII of the cerebellum were specifically activated during fast movements, both in imagination and execution. We show that the selection of the neural networks underlying voluntary movement of the foot is depending on the speed strategy and is sensitive to execution versus imagery. Moreover, to the light of surprising recent findings in monkeys showing that the vermis should no longer be considered as entirely isolated from the cerebral cortex (Coffman et al., 2011 [2]), we suggest that the anterior vermis contributes to computational aspects of fast commands, whereas more lateral cerebellar superior lobe and lobule VIII would regulate patterning and sequencing of submovements in conjunction with movement rate. We also suggest that execution of overt slow movements, which strongly involves prefrontal executive cortex as during motor mental imagery, is associated with conscious mental representation of the ongoing movements.

Multimodal BCI-mediated FES suppression of pathological tremor.

Tremor constitutes the most common movement disorder; in fact 14.5% of population between 50 to 89 years old suffers from it. Moreover, 65% of patients with upper limb tremor report disability when performing their activities of daily living (ADL). Unfortunately, 25% of patients do not respond to drugs or neurosurgery. In this regard, TREMOR project proposes functional compensation of upper limb tremors with a soft wearable robot that applies biomechanical loads through functional electrical stimulation (FES) of muscles. This wearable robot is driven by a Brain Neural Computer Interface (BNCI). This paper presents a multimodal BCI to assess generation, transmission and execution of both volitional and tremorous movements based on electroencephalography (EEG), electromyography (EMG) and inertial sensors (IMUs). These signals are combined to obtain: 1) the intention to perform a voluntary movement from cortical activity (EEG), 2) tremor onset, and an estimation of tremor frequency from muscle activation (EMG), and 3) instantaneous tremor amplitude and frequency from kinematic measurements (IMUs). Integration of this information will provide control signals to drive the FES-based wearable robot.

Past, present and future therapeutics for cerebellar ataxias.

Cerebellar ataxias are a group of disabling neurological disorders. Patients exhibit a cerebellar syndrome and can also present with extra-cerebellar deficits, namely pigmentary retinopathy, extrapyramidal movement disorders, pyramidal signs, cortical symptoms (seizures, cognitive impairment/behavioural symptoms), and peripheral neuropathy. Recently, deficits in cognitive operations have been unraveled. Cerebellar ataxias are heterogeneous both at the phenotypic and genotypic point of view. Therapeutical trials performed during these last 4 decades have failed in most cases, in particular because drugs were not targeting a deleterious pathway, but were given to counteract putative defects in neurotransmission. The identification of the causative mutations of many hereditary ataxias, the development of relevant animal models and the recent identifications of the molecular mechanisms underlying ataxias are impacting on the development of new drugs. We provide an overview of the pharmacological treatments currently used in the clinical practice and we discuss the drugs under development.

Pregabalin antagonizes copper-induced toxicity in the brain: in vitro and in vivo studies.

BACKGROUND: Copper plays key roles in brain metabolism. Disorders of copper metabolism impact on neural signaling. The intracellular and extracellular concentrations of copper are tightly regulated. Pregabalin is a drug with multiple modes of action and has a high-affinity binding site for the alpha2delta subunit of voltage-gated calcium channels. METHODS: Assessment of neuroprotective effects of pregabalin using cell culture, transcription studies, microdialysis and neurophysiological assessment in rats. RESULTS: In vitro, copper decreased markedly the survival of neuronal cells and enhanced the production of nitric oxide (NO). Transcription of NO synthase (NOS) 1-3 and PGC-1a (a key regulator of mitochondrial biogenesis) was activated. In vivo, copper impaired the NMDA-mediated regulation of glutamate in the brain, increased the production of NO and enhanced markedly the excitability of the motor cortex. Pregabalin had antagonistic effects both in vitro and in vivo. CONCLUSION: Our experiments highlight that pregabalin antagonizes the neurotoxic effects of copper. We argue that pregabalin exerts neuroprotective effects by silencing the overexcitability state induced by copper. We propose a possible use of pregabalin for treatment of disruption of copper homeostasis.

A possible mechanism for the beneficial effect of ethanol in essential tremor.

BACKGROUND: Essential tremor is one of the most common movement disorders in elderly people. The hypothesis of a disregulation of N-methyl-D-aspartate (NMDA) pathways has been suggested. It was shown experimentally that infusion of NMDA in cerebellar nuclei down-regulates glutamate release. METHODS: We assessed the effects of intranuclear administration of harmaline on the NMDA-mediated regulation of glutamate in rats using reverse dialysis. We hypothesized that ethanol, which improves essential tremor in the clinic, antagonizes the effect of harmaline upon glutamatergic transmission. We tested the interaction of ethanol and harmaline upon glycerol (a marker of membrane turn-over), lactate, and pyruvate concentrations. RESULTS: Harmaline increased the concentrations of glutamate and impaired the NMDA-mediated regulation of glutamate. Ethanol decreased the concentrations of glutamate during NMDA stimulation in case of pre-administration with harmaline. Concentrations of glycerol rose with harmaline. Glycerol levels markedly decreased during NMDA infusion when inhibitors of nitric oxide synthase, alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate antagonists or NMDA antagonists were administered. Harmaline increased lactate/pyruvate ratios during NMDA infusion but these ratios returned to normal values in presence of ethanol. DISCUSSION: We provide a possible mechanism for the beneficial effect of ethanol on essential tremor. The concept of glutamatergic disregulation underlying essential tremor is highlighted. Consequences for our understanding of essential tremor are discussed.

Effects of inertia and wrist oscillations on contralateral neurological postural tremor using the wristalyzer, a new myohaptic device.

Upper limb postural tremor consists of mechanical-reflex and central-neurogenic oscillations, superimposed upon a background of irregular fluctuations in muscle force. Muscle spindles play key-roles in the information flow to supra-spinal and spinal generators. Oscillations were delivered using a new generation portable myohaptic device, called ldquowristalyzer,rdquo taking into account the ergonomy of upper limbs and allowing a fine adjustment to each configuration of upper limb segments. The nominal torque of the first generation device is 4 Nm, with a maximal rotation velocity of 300 degrees/s and a range of motion of plusmn45 degrees. Reliability was assessed in basal condition and during loading conditions. We assessed the effects of the addition of inertia on postural tremor of the finger in a group of 26 neurological patients and the effects of wrist oscillations upon contralateral postural tremor in 6 control subjects and in 7 neurological patients exhibiting a postural tremor. Patients showed two different behaviors in response to inertia and exhibited an increased variability of postural tremor during fast oscillations (13.3 Hz). One patient with overactivity of the olivocerebellar pathways exhibited a drop in the peak frequency of more than 20%. The relative power of the 8-12 Hz subband was significantly higher in controls both in basal condition and during oscillations (p = 0.028 and p = 0.015, respectively). The second generation wristalyzer allows to investigate the effects of mechanical oscillations up to frequency of 50 Hz. This mechatronic device can assess the responsiveness of tremor generators to stimulation of muscle spindles and biomechanical loading. Potential applications are the monitoring of dysmetria under various inertial or damping conditions, the assessment of rigidity in Parkinson's disease and the characterization of voluntary muscle force.

Design and validation of a rehabilitation robotic exoskeleton for tremor assessment and suppression.

Exoskeletons are mechatronic systems worn by a person in such a way that the physical interface permits a direct transfer of mechanical power and exchange of information. Upper limb robotic exoskeletons may be helpful for people with disabilities and/or limb weakness or injury. Tremor is the most common movement disorder in neurological practice. In addition to medication, rehabilitation programs, and deep brain stimulation, biomechanical loading has appeared as a potential tremor suppression alternative. This paper introduces the robotic exoskeleton called WOTAS (wearable orthosis for tremor assessment and suppression) that provides a means of testing and validating nongrounded control strategies for orthotic tremor suppression. This paper describes in detail the general concept for WOTAS, outlining the special features of the design and selection of system components. Two control strategies developed for tremor suppression with exoskeletons are described. These two strategies are based on biomechanical loading and notch filtering the tremor through the application of internal forces. Results from experiments using these two strategies on patients with tremor are summarized. Finally, results from clinical trials are presented, which indicate the feasibility of ambulatory mechanical suppression of tremor.

Novel missense mutation in the caveolin-3 gene in a Belgian family with rippling muscle disease.

Rippling muscle disease (RMD) is a rare muscle disorder characterised by muscle stiffness, exercise induced myalgia, and cramp-like sensations. It is genetically heterogeneous and can be acquired, but most cases show autosomal dominant inheritance due to mutations in the caveolin-3 (CAV3) gene. We report a novel heterozygous missense mutation in CAV3 in a Belgian family with autosomal dominant RMD. A 40 year old woman complained of fatigue, exercise induced muscle pain, and muscle cramps since the age of 35. Neurological examination revealed percussion induced rapid muscle contractions (PIRCs) and localised muscle mounding on percussion; muscle rippling was not observed. Creatine kinase (CK) was elevated but electromyography and nerve conduction studies were normal. Fluorescence immunohistochemistry revealed reduced caveolin-3 and dysferlin staining in a quadriceps muscle biopsy. Western blot analysis confirmed severely reduced caveolin-3 levels, whereas dysferlin was normal. Sequence analysis of the two coding exons of CAV3 revealed a hitherto unreported heterozygous C82A transversion in the first exon, predicting a Pro28Thr amino acid exchange. Thr patient's first degree relatives did not present with neuromuscular complaints, but PIRCs, muscle mounding, and muscle rippling were found in the mother, who also carried the CAV3 mutation.