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      The mystery of the cerebellum: clues from experimental and clinical observations

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          Abstract

          The cerebellum has a striking homogeneous cytoarchitecture and participates in both motor and non-motor domains. Indeed, a wealth of evidence from neuroanatomical, electrophysiological, neuroimaging and clinical studies has substantially modified our traditional view on the cerebellum as a sole calibrator of sensorimotor functions. Despite the major advances of the last four decades of cerebellar research, outstanding questions remain regarding the mechanisms and functions of the cerebellar circuitry. We discuss major clues from both experimental and clinical studies, with a focus on rodent models in fear behaviour, on the role of the cerebellum in motor control, on cerebellar contributions to timing and our appraisal of the pathogenesis of cerebellar tremor. The cerebellum occupies a central position to optimize behaviour, motor control, timing procedures and to prevent body oscillations. More than ever, the cerebellum is now considered as a major actor on the scene of disorders affecting the CNS, extending from motor disorders to cognitive and affective disorders. However, the respective roles of the mossy fibres, the climbing fibres, cerebellar cortex and cerebellar nuclei remains unknown or partially known at best in most cases. Research is now moving towards a better definition of the roles of cerebellar modules and microzones. This will impact on the management of cerebellar disorders.

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          Most cited references91

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          What makes us tick? Functional and neural mechanisms of interval timing.

          Time is a fundamental dimension of life. It is crucial for decisions about quantity, speed of movement and rate of return, as well as for motor control in walking, speech, playing or appreciating music, and participating in sports. Traditionally, the way in which time is perceived, represented and estimated has been explained using a pacemaker-accumulator model that is not only straightforward, but also surprisingly powerful in explaining behavioural and biological data. However, recent advances have challenged this traditional view. It is now proposed that the brain represents time in a distributed manner and tells the time by detecting the coincidental activation of different neural populations.
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            A theory of cerebellar cortex.

            D. Marr (1969)
            1. A detailed theory of cerebellar cortex is proposed whose consequence is that the cerebellum learns to perform motor skills. Two forms of input-output relation are described, both consistent with the cortical theory. One is suitable for learning movements (actions), and the other for learning to maintain posture and balance (maintenance reflexes).2. It is known that the cells of the inferior olive and the cerebellar Purkinje cells have a special one-to-one relationship induced by the climbing fibre input. For learning actions, it is assumed that:(a) each olivary cell responds to a cerebral instruction for an elemental movement. Any action has a defining representation in terms of elemental movements, and this representation has a neural expression as a sequence of firing patterns in the inferior olive; and(b) in the correct state of the nervous system, a Purkinje cell can initiate the elemental movement to which its corresponding olivary cell responds.3. Whenever an olivary cell fires, it sends an impulse (via the climbing fibre input) to its corresponding Purkinje cell. This Purkinje cell is also exposed (via the mossy fibre input) to information about the context in which its olivary cell fired; and it is shown how, during rehearsal of an action, each Purkinje cell can learn to recognize such contexts. Later, when the action has been learnt, occurrence of the context alone is enough to fire the Purkinje cell, which then causes the next elemental movement. The action thus progresses as it did during rehearsal.4. It is shown that an interpretation of cerebellar cortex as a structure which allows each Purkinje cell to learn a number of contexts is consistent both with the distributions of the various types of cell, and with their known excitatory or inhibitory natures. It is demonstrated that the mossy fibre-granule cell arrangement provides the required pattern discrimination capability.5. The following predictions are made.(a) The synapses from parallel fibres to Purkinje cells are facilitated by the conjunction of presynaptic and climbing fibre (or post-synaptic) activity.(b) No other cerebellar synapses are modifiable.(c) Golgi cells are driven by the greater of the inputs from their upper and lower dendritic fields.6. For learning maintenance reflexes, 2(a) and 2(b) are replaced by2'. Each olivary cell is stimulated by one or more receptors, all of whose activities are usually reduced by the results of stimulating the corresponding Purkinje cell.7. It is shown that if (2') is satisfied, the circuit receptor --> olivary cell --> Purkinje cell --> effector may be regarded as a stabilizing reflex circuit which is activated by learned mossy fibre inputs. This type of reflex has been called a learned conditional reflex, and it is shown how such reflexes can solve problems of maintaining posture and balance.8. 5(a), and either (2) or (2') are essential to the theory: 5(b) and 5(c) are not absolutely essential, and parts of the theory could survive the disproof of either.
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              The image of time: a voxel-wise meta-analysis.

              Although there has been an explosion of interest in the neural correlates of time perception during the past decade, substantial disagreement persists regarding the structures that are relevant to interval timing. We addressed this important issue by conducting a comprehensive, voxel-wise meta-analysis using the activation likelihood estimation algorithm; this procedure models each stereotactic coordinate as a 3D Gaussian distribution, then tests the likelihood of activation across all voxels in the brain (Turkeltaub et al., 2002). We included 446 sets of activation foci across 41 studies of timing that report whole-brain analyses. We divided the data set along two dimensions: stimulus duration (sub- vs. supra-second) and nature of response (motor vs. perceptual). Our meta-analyses revealed dissociable neural networks for the processing of duration with motor or perceptual components. Sub-second timing tasks showed a higher propensity to recruit sub-cortical networks, such as the basal ganglia and cerebellum, whereas supra-second timing tasks were more likely to activate cortical structures, such as the SMA and prefrontal cortex. We also detected a differential pattern of activation likelihood in basal ganglia structures, depending on the interval and task design. Finally, a conjunction analysis revealed the SMA and right inferior frontal gyrus as the only structures with significant voxels across all timing conditions. These results suggest that the processing of temporal information is mediated by a distributed network that can be differentially engaged depending on the task requirements.
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                Author and article information

                Contributors
                mmanto@ulb.ac.be
                Journal
                Cerebellum Ataxias
                Cerebellum Ataxias
                Cerebellum & Ataxias
                BioMed Central (London )
                2053-8871
                29 March 2018
                29 March 2018
                2018
                : 5
                : 8
                Affiliations
                [1 ]ISNI 0000 0004 1936 7603, GRID grid.5337.2, School of Physiology, Pharmacology and Neuroscience, Biomedical Sciences Building, , University of Bristol, Tankard’s Close, University Walk, ; Bristol, BS8 1TD UK
                [2 ]ISNI 0000 0001 2194 0956, GRID grid.10267.32, First Department of Neurology, , Faculty of Medicine, Masaryk University and St. Anne’s Teaching Hospital, ; Brno, Czech Republic
                [3 ]ISNI 0000000419368657, GRID grid.17635.36, Department of Neurology, , School of Medicine, University of Minnesota, ; Minneapolis, USA
                [4 ]GRID grid.419605.f, Department of Neurology, , National Institute of Clinical Neurosciences, ; Amerikai út 57, Budapest, 1145 Hungary
                [5 ]ISNI 0000 0001 0942 9821, GRID grid.11804.3c, Department of Neurology, , Semmelweis University, ; Üllői út 26, Budapest, 1083 Hungary
                [6 ]ISNI 0000 0001 0942 9821, GRID grid.11804.3c, János Szentágothai Doctoral School of Neurosciences, Semmelweis University, ; Üllői út 26, Budapest, 1083 Hungary
                [7 ]ISNI 0000 0004 0647 2148, GRID grid.424470.1, FNRS ULB-Erasme, ; 808 Route de Lennik, 1070 Bruxelles, Belgium
                [8 ]ISNI 0000 0001 2184 581X, GRID grid.8364.9, Service des Neurosciences, UMons, ; 7000 Mons, Belgium
                [9 ]ISNI 0000 0001 0124 3248, GRID grid.413871.8, Department of Neurology, , Centre Hospitalier Universitaire (CHU) de Charleroi, ; 6000 Charleroi, Belgium
                [10 ]Laboratoire de Médecine Expérimentale, Site Vésale, ULB Unité 222, 6110 Montigny-le-Tilleul, Belgium
                Article
                87
                10.1186/s40673-018-0087-9
                5877388
                29610671
                d267802f-d6fb-4f06-ae60-c39803f32bb8
                © The Author(s). 2018

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 5 December 2017
                : 15 March 2018
                Funding
                Funded by: FNRS-FRS
                Award ID: Support to MM
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100000268, Biotechnology and Biological Sciences Research Council;
                Award ID: Support to CL
                Award Recipient :
                Categories
                Review
                Custom metadata
                © The Author(s) 2018

                cerebellum,anatomy,history,fear,cognition,motor,timing,tremor
                cerebellum, anatomy, history, fear, cognition, motor, timing, tremor

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