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.

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.

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.