Mario Manto

Consensus Paper: The Cerebellum's Role in Movement and Cognition

While the cerebellums role in motor function is well recognized, the nature of its concurrent role in cognitive function remains considerably less clear. The current consensus paper gathers diverse views on a variety of important roles played by the cerebellum across a range of cognitive and emotional functions. This paper considers the cerebellum in relation to neurocognitive development, language function, working memory, executive function, and the development of cerebellar internal control models and reflects upon some of the ways in which better understanding the cerebellums status as a “supervised learning machine” can enrich our ability to understand human function and adaptation. As all contributors agree that the cerebellum plays a role in cognition, there is also an agreement that this conclusion remains highly inferential. Many conclusions about the role of the cerebellum in cognition originate from applying known information about cerebellar contributions to the coordination and quality of movement. These inferences are based on the uniformity of the cerebellums compositional infrastructure and its apparent modular organization. There is considerable support for this view, based upon observations of patients with pathology within the cerebellum.

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.

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 Altering 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

Generation of functional thyroid from embryonic stem cells

The primary function of the thyroid gland is to metabolize iodide by synthesizing thyroid hormones, which are critical regulators of growth, development and metabolism in almost all tissues. So far, research on thyroid morphogenesis has been missing an efficient stem-cell model system that allows for the in vitro recapitulation of the molecular and morphogenic events regulating thyroid follicular-cell differentiation and subsequent assembly into functional thyroid follicles. Here we report that a transient overexpression of the transcription factors NKX2-1 and PAX8 is sufficient to direct mouse embryonic stem-cell differentiation into thyroid follicular cells that organize into three-dimensional follicular structures when treated with thyrotropin. These in vitro-derived follicles showed appreciable iodide organification activity. Importantly, when grafted in vivo into athyroid mice, these follicles rescued thyroid hormone plasma levels and promoted subsequent symptomatic recovery. Thus, mouse embryonic stem cells can be induced to differentiate into thyroid follicular cells in vitro and generate functional thyroid tissue.

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.

Handbook of the cerebellum and cerebellar disorders

The cerebellar primordium develops dorsally at an intermediate anteroposterior (AP) level of the neural tube. Its size is modulated by the early anteriorizing and posteriorizing signals, which pattern the neural tube. Two important signaling centers, the midbrain–hindbrain organizer and the roof plate, intersect at the level of the cerebellar anlage and control its positioning, differentiation, growth, survival, and patterning. Neural tube bending in the pontine region induces a widening of the fourth ventricle, which is made possible by choroid plexus differentiation and extension. As a consequence of these morphogenetic changes, the AP axis of the cerebellar primordium is rotated by 90 , and the cerebellar vermis and hemispheres derive from the anterior and posterior parts of the early cerebellar plate, respectively. The cerebellar plate is progressively subdivided along its dorsoventral axis into distinct domains, which generate subsets of cerebellar neurons according to their neurotransmitter phenotype. The roof plate marked by Gdf7 expression is at the origin of choroid plexus cells but does not contribute neurons or glia to the cerebellum. The rhombic lip, marked by Atoh1 expression, produces all the glutamatergic neurons of the cerebellum and a large number of non-cerebellar neurons. Finally, the ventral cerebellar neuroepithelium, marked by Ptf1a expression, generates all the GABAergic neurons and can be further subdivided into two progenitor domains, devoted to the production of Purkinje cells and GABAergic projection neurons of the deep M. Wassef Institut de Biologie de l’Ecole Normale Supérieure (IBENS), 46 rue d’Ulm, 75005 Paris, France and CNRS UMR 8197, 46 rue d’Ulm, 75005 Paris, France and INSERM U1024, 46 rue d’Ulm, 75005 Paris, France e-mail: wassef@biologie.ens.fr M. Manto, D.L. Gruol, J.D. Schmahmann, N. Koibuchi, F. Rossi (eds.), Handbook of the Cerebellum and Cerebellar Disorders, DOI 10.1007/978-94-007-1333-8_1, # Springer Science+Business Media Dordrecht 2013 3 cerebellar nuclei. The so-called cerebellar primordium is not restricted to the production of cerebellar neurons but contributes to a large number of nuclei in the isthmic region.

Cerebellum: links between development, developmental disorders and motor learning

The study of the links and interactions between development and motor learning has noticeable implications for the understanding and management of neurodevelopmental disorders. This is particularly relevant for the cerebellum which is critical for sensorimotor learning. The olivocerebellar pathway is a key pathway contributing to learning of motor skills. Its developmental maturation and remodeling are being unraveled. Advances in genetics have led to major improvements in our appraisal of the genes involved in cerebellar development, especially studies in mutant mice. Cerebellar neurogenesis is compartmentalized in relationship with neurotransmitter fate. The Engrailed-2 gene is a major actor of the specification of cerebellar cell types and late embryogenic morphogenesis. Math1, expressed by the rhombic lip, is required for the genesis of glutamatergic neurons. Mutants deficient for the transcription factor Ptf1a display a lack of Purkinje cells and gabaergic interneurons. Rora gene contributes to the developmental signaling between granule cells and Purkinje neurons. The expression profile of sonic hedgehog in postnatal stages determines the final size/shape of the cerebellum. Genes affecting the development impact upon the physiological properties of the cerebellar circuits. For instance, receptors are developmentally regulated and their action interferes directly with developmental processes. Another field of research which is expanding relates to very preterm neonates. They are at risk for cerebellar lesions, which may themselves impair the developmental events. Very preterm neonates often show sensori-motor deficits, highlighting another major link between impaired developments and learning deficiencies. Pathways playing a critical role in cerebellar development are likely to become therapeutical targets for several neurodevelopmental disorders.

Topography of Cerebellar Deficits in Humans

The cerebellum is a key-piece for information processing and is involved in numerous motor and nonmotor activities, thanks to the anatomical characteristics of the circuitry, the enormous computational capabilities and the high connectivity to other brain areas. Despite its uniform cytoarchitecture, cerebellar circuitry is segregated into functional zones. This functional parcellation is driven by the connectivity and the anatomo-functional heterogeneity of the numerous extra-cerebellar structures linked to the cerebellum, principally brain cortices, precerebellar nuclei and spinal cord. Major insights into cerebellar functions have been gained with a detailed analysis of the cerebellar outputs, with the evidence that fundamental aspects of cerebrocerebellar operations are the closed-loop circuit and the predictions of future states. Cerebellar diseases result in disturbances of accuracy of movements and lack of coordination. The cerebellar syndrome includes combinations of oculomotor disturbances, dysarthria and other speech deficits, ataxia of limbs, ataxia of stance and gait, as well as often more subtle cognitive/behavioral impairments. Our understanding of the corresponding anatomo-functional maps for the human cerebellum is continuously improving. We summarize the topography of the clinical deficits observed in cerebellar patients and the growing evidence of a regional subdivision into motor, sensory, sensorimotor, cognitive and affective domains. The recently described topographic dichotomy motor versus nonmotor cerebellum based upon anatomical, functional and neuropsychological studies is also discussed.

PGC-1alpha Down-Regulation Affects the Antioxidant Response in Friedreich's Ataxia

Background Cells from individuals with Friedreichs ataxia (FRDA) show reduced activities of antioxidant enzymes and cannot up-regulate their expression when exposed to oxidative stress. This blunted antioxidant response may play a central role in the pathogenesis. We previously reported that Peroxisome Proliferator Activated Receptor Gamma (PPARγ) Coactivator 1-alpha (PGC-1α), a transcriptional master regulator of mitochondrial biogenesis and antioxidant responses, is down-regulated in most cell types from FRDA patients and animal models. Methodology/Principal Findings We used primary fibroblasts from FRDA patients and the knock in-knock out animal model for the disease (KIKO mouse) to determine basal superoxide dismutase 2 (SOD2) levels and the response to oxidative stress induced by the addition of hydrogen peroxide. We measured the same parameters after pharmacological stimulation of PGC-1α. Compared to control cells, PGC-1α and SOD2 levels were decreased in FRDA cells and did not change after addition of hydrogen peroxide. PGC-1α direct silencing with siRNA in control fibroblasts led to a similar loss of SOD2 response to oxidative stress as observed in FRDA fibroblasts. PGC-1α activation with the PPARγ agonist (Pioglitazone) or with a cAMP-dependent protein kinase (AMPK) agonist (AICAR) restored normal SOD2 induction. Treatment of the KIKO mice with Pioglitazone significantly up-regulates SOD2 in cerebellum and spinal cord. Conclusions/Significance PGC-1α down-regulation is likely to contribute to the blunted antioxidant response observed in cells from FRDA patients. This response can be restored by AMPK and PPARγ agonists, suggesting a potential therapeutic approach for FRDA.

Cerebellar Transcranial Direct Current Stimulation (ctDCS) A Novel Approach to Understanding Cerebellar Function in Health and Disease

The cerebellum is critical for both motor and cognitive control. Dysfunction of the cerebellum is a component of multiple neurological disorders. In recent years, interventions have been developed that aim to excite or inhibit the activity and function of the human cerebellum. Transcranial direct current stimulation of the cerebellum (ctDCS) promises to be a powerful tool for the modulation of cerebellar excitability. This technique has gained popularity in recent years as it can be used to investigate human cerebellar function, is easily delivered, is well tolerated, and has not shown serious adverse effects. Importantly, the ability of ctDCS to modify behavior makes it an interesting approach with a potential therapeutic role for neurological patients. Through both electrical and non-electrical effects (vascular, metabolic) ctDCS is thought to modify the activity of the cerebellum and alter the output from cerebellar nuclei. Physiological studies have shown a polarity-specific effect on the modulation of cerebellar–motor cortex connectivity, likely via cerebellar–thalamocortical pathways. Modeling studies that have assessed commonly used electrode montages have shown that the ctDCS-generated electric field reaches the human cerebellum with little diffusion to neighboring structures. The posterior and inferior parts of the cerebellum (i.e., lobules VI-VIII) seem particularly susceptible to modulation by ctDCS. Numerous studies have shown to date that ctDCS can modulate motor learning, and affect cognitive and emotional processes. Importantly, this intervention has a good safety profile; similar to when applied over cerebral areas. Thus, investigations have begun exploring ctDCS as a viable intervention for patients with neurological conditions.