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Restoration of damaged central nervous system structures, functional recovery, and prevention of neuronal loss during neurodegenerative diseases are major objectives in cerebellar research. The highly organized anatomical structure of the cerebellum with numerous inputs/outputs, the complexity of cerebellar functions, and the large spectrum of cerebellar ataxias render therapies of cerebellar disorders highly challenging. There are currently several therapeutic approaches including motor rehabilitation, neuroprotective drugs, non-invasive cerebellar stimulation, molecularly based therapy targeting pathogenesis of the disease, and neurotransplantation. We discuss the goals and possible beneficial mechanisms of transplantation therapy for cerebellar damage and its limitations and factors determining outcome. [ABSTRACT FROM AUTHOR]

Autosomal recessive cerebellar ataxias (ARCAs) are inherited neurological disorders that can affect both the central and peripheral nervous systems. To assess the effects of interventions according to the perception of people affected, patient-reported outcome measures (PROMs) must be available. This paper presents the development process of the Person-Reported Ataxia Impact Scale (PRAIS), a new PROM in recessive ataxias, and the documentation of its content validity, interpretability, and construct validity (structural and discriminant). The development followed the PROMIS framework and the Food and Drug Administration guidelines. A mixed-method study design was used to develop the PROM. A systematic review of the literature, semistructured interviews, and discussion groups was conducted to constitute an item pool. Experts' consultation helped formulate items, and the questionnaire was sent online to be completed by people affected. Statistical analyses were performed to assess the structural and discriminant validity. A total of 125 people affected by recessive ataxia completed the questionnaire. The factor analysis confirmed the three components: physical functions and activities, mental functions, and social functions. The statistical analysis showed that it can discriminate between stages of mobility and level of autonomy. It showed very good levels of internal consistency (0.79 to 0.89). The Person-Reported Ataxia Impact Scale (PRAIS) is a 38-item questionnaire that assesses the manifestations and impacts of the disease according to the perception of people affected by recessive ataxia. It can be used in clinical and research settings. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a progressive disease that often affects the cerebellum. It is characterised by demyelination, inflammation, and neurodegeneration within the central nervous system. Damage to the cerebellum in MS is associated with increased disability and decreased quality of life. Symptoms include gait and balance problems, motor speech disorder, upper limb dysfunction, and oculomotor difficulties. Monitoring symptoms is crucial for effective management of MS. A combination of clinical, neuroimaging, and task-based measures is generally used to diagnose and monitor MS. This paper reviews the present and new tools used by clinicians and researchers to assess cerebellar impairment in people with MS (pwMS). It also describes recent advances in digital and home-based monitoring for people with MS. [ABSTRACT FROM AUTHOR]

During forward swinging of the arm, the central nervous system must anticipate the effect of upraising upon the body. Little is known about the cerebellar network that coordinates these anticipatory postural adjustments (APAs). Stimulating different cerebellar regions with transcranial direct current stimulation (tDCS) and with different polarities modulated the APAs. We used surface electromyography (sEMG) to measure muscle activities in a bilateral rapid shoulder flexion task. The onset of APAs was altered after tDCS over the vermis, while the postural stability and the kinematics of arm raising were not affected. To our knowledge, this is the first human cerebellar-tDCS (c-tDCS) study to separate cerebellar involvement in core muscle APAs in bilateral rapid shoulder flexion. These data contribute to our understanding of the cerebellar network supporting APAs in healthy adults. Modulated APAs of the erector spinae by tDCS on the vermis may be related to altered cerebellar brain inhibition (CBI), suggesting the importance of the vermal-cerebral connections in APAs regulation. [ABSTRACT FROM AUTHOR]

The cerebellum is ontogenetically one of the first structures to develop in the central nervous system; nevertheless, it has been only recently reconsidered for its significant neurobiological, functional, and clinical relevance in humans. Thus, it has been a relatively under-studied compared to the cerebrum. Currently, non-invasive imaging modalities can barely reach the necessary resolution to unfold its entire, convoluted surface, while only histological analyses can reveal local information at the micrometer scale. Herein, we used the BigBrain dataset to generate area and point-wise thickness measurements for all layers of the cerebellar cortex and for each lobule in particular. We found that the overall surface area of the cerebellar granular layer (including Purkinje cells) was 1,732 cm2 and the molecular layer was 1,945 cm2. The average thickness of the granular layer is 0.88 mm (± 0.83) and that of the molecular layer is 0.32 mm (± 0.08). The cerebellum (both granular and molecular layers) is thicker at the depth of the sulci and thinner at the crowns of the gyri. Globally, the granular layer is thicker in the lateral-posterior-inferior region than the medial-superior regions. The characterization of individual layers in the cerebellum achieved herein represents a stepping-stone for investigations interrelating structural and functional connectivity with cerebellar architectonics using neuroimaging, which is a matter of considerable relevance in basic and clinical neuroscience. Furthermore, these data provide templates for the construction of cerebellar topographic maps and the precise localization of structural and functional alterations in diseases affecting the cerebellum. [ABSTRACT FROM AUTHOR]

Cerebellar hypoplasia and dysplasia encompass a group of clinically and genetically heterogeneous disorders frequently associated with neurodevelopmental impairment. The Neuron Navigator 2 (NAV2) gene (MIM: 607,026) encodes a member of the Neuron Navigator protein family, widely expressed within the central nervous system (CNS), and particularly abundant in the developing cerebellum. Evidence across different species supports a pivotal function of NAV2 in cytoskeletal dynamics and neurite outgrowth. Specifically, deficiency of Nav2 in mice leads to cerebellar hypoplasia with abnormal foliation due to impaired axonal outgrowth. However, little is known about the involvement of the NAV2 gene in human disease phenotypes. In this study, we identified a female affected with neurodevelopmental impairment and a complex brain and cardiac malformations in which clinical exome sequencing led to the identification of NAV2 biallelic truncating variants. Through protein expression analysis and cell migration assay in patient-derived fibroblasts, we provide evidence linking NAV2 deficiency to cellular migration deficits. In model organisms, the overall CNS histopathology of the Nav2 hypomorphic mouse revealed developmental anomalies including cerebellar hypoplasia and dysplasia, corpus callosum hypo-dysgenesis, and agenesis of the olfactory bulbs. Lastly, we show that the NAV2 ortholog in Drosophila, sickie (sick) is widely expressed in the fly brain, and sick mutants are mostly lethal with surviving escapers showing neurobehavioral phenotypes. In summary, our results unveil a novel human neurodevelopmental disorder due to genetic loss of NAV2, highlighting a critical conserved role of the NAV2 gene in brain and cerebellar development across species. [ABSTRACT FROM AUTHOR]

Gamma-aminobutyric acid (GABA) is a major inhibitory neurotransmitter in the central nervous system, synthesized by two isoforms of glutamate decarboxylase (GAD): GAD65 and GAD67. GABA may act as a trophic factor during brain development, but its contribution to the development and maturation of cerebellar neural circuits is not known. To understand the roles of GABA in cerebellar organization and associated functions in motor coordination and balance, we examined GAD65 conventional knock out (KO) mice and mice in which GAD67 was eliminated in parvalbumin-expressing neurons (PV-Cre; GAD67flox/flox mice). We found aberrant subcellular localization of the Shaker-type K channel Kv1.1 in basket cell collaterals of PV-Cre; GAD67flox/flox mice and abnormal projections from basket cells to Purkinje cells in both mouse strains. We also found that altered synaptic properties of basket cell terminals to Purkinje cells in PV-Cre; GAD67flox/flox mice. Furthermore, PV-Cre; GAD67flox/flox mice exhibited abnormal motor coordination in the rotarod test. These results indicate that GABA signaling in the cerebellum is critical for establishing appropriate connections between basket cells and Purkinje cells and is associated with motor coordination in mice. [ABSTRACT FROM AUTHOR]

The cerebellum contains the highest density of protein kinase C (PKC) in the central nervous system. PKCγ, the major isotype accounting for over half of the PKCs in the cerebellum, is expressed exclusively in Purkinje cells (PCs). Inactivated PKCγ, which is localized in the cytoplasm of PC dendrites and soma, begins to translocate to the cell membrane upon activation. However, the physiological conditions that induce PKCγ translocation in PC remain largely unknown. Here, we virally expressed PKCγ-GFP in PCs and examined the conditions that induced its translocation to PC dendrites by whole-cell patch clamp analysis combined with confocal GFP fluorescence imaging. A single or repetitive (150 pulses at 5 Hz for 30 s) electrical stimulation to a climbing fiber (CF), which produced a complex spike(s) in PC, failed to induce translocation of PKCγ-GFP to the dendritic shaft of PCs. Direct current injection (+ 2 nA for 3 s) to PC also did not induce the translocation, although PCs generated simple spikes continuously at high rates. In contrast, high-frequency parallel fiber (PF) stimulation (50 pulses at 50 Hz for 1 s), which triggered action potentials followed by sustained depolarization (known as mGluR1-mediated slow depolarization), caused translocation of cytoplasmic PKCγ-GFP to the membrane. Low-frequency PF stimulation (150 pulses at 5 Hz for 30 s) induced continuous simple spike firing but did not induce translocation. These results suggest that CF-triggered depolarization, which causes Ca2+ influx through voltage-gated Ca2+ channels throughout PC dendrites and somas, is insufficient to induce the translocation of PKCγ, instead requiring high-frequency PF stimulation that activates mGluR1. [ABSTRACT FROM AUTHOR]

Essential tremor (ET) has recently been reconceptualized by many as a degenerative disease of the cerebellum. Until now, though, there has been no attempt to frame it within the context of these diseases. Here, we compare the clinical and postmortem features of ET with other cerebellar degenerations, thereby placing it within the broader context of these diseases. Action tremor is the hallmark feature of ET. Although often underreported in the spinocerebellar ataxias (SCAs), action tremors occur, and it is noteworthy that in SCA12 and 15, they are highly prevalent, often severe, and can be the earliest disease manifestation, resulting in an initial diagnosis of ET in many cases. Intention tremor, sometimes referred to as "cerebellar tremor," is a common feature of ET and many SCAs. Other features of cerebellar dysfunction, gait ataxia and eye motion abnormalities, are seen to a mild degree in ET and more markedly in SCAs. Several SCAs (e.g., SCA5, 6, 14, and 15), like ET, follow a milder and more protracted disease course. In ET, numerous postmortem changes have been localized to the cerebellum and are largely confined to the cerebellar cortex, preserving the cerebellar nuclei. Purkinje cell loss is modest. Similarly, in SCA3, 12, and 15, Purkinje cell loss is limited, and in SCA12 and 15, there is preservation of cerebellar nuclei and relative sparing of other central nervous system regions. Both clinically and pathologically, there are numerous similarities and intersection points between ET and other disorders of cerebellar degeneration. [ABSTRACT FROM AUTHOR]

Type I Chiari malformation (CMI) is a neurological condition in which the cerebellar tonsils descend into the cervical spinal subarachnoid space resulting in cervico-medullary compression. Early case-control investigations have indicated cognitive deficits in the areas of attention, memory, processing speed, and visuospatial function. The present study further examined cognitive and emotional processing deficits associated with CMI using a dual-task paradigm. Nineteen CMI patients were recruited during pre-surgical consultation and 19 matched control participants identified emotional expressions in separate single and asynchronous dual-task designs. To extend earlier behavioral studies of cognitive effects in CMI, we recorded event-related potentials (ERPs) in the dual-task design. Though response times were slower for CMI patients across the two tasks, behavioral and ERP analyses indicated that patients did not differ from matched controls in the ability to allocate attentional resources between the two tasks. P1 ERP component analyses provided no indication of an emotional arousal deficit in our CMI sample while P3 ERP component analyses suggested a CMI-related deficit in emotional regulation. P3 analysis also yielded evidence for a frontalization of neurophysiological activity in CMI patients. Pain and related depression and anxiety factors accounted for CMI deficits in single-task, but not dual-task, response times. Results are consistent with a dysfunctional fronto-parietal attentional network resulting from either the indirect effects of chronic pain or the direct effects of CMI pathophysiology stemming from cervico-medullary compression. [ABSTRACT FROM AUTHOR]

The cerebellum characteristically has the capacity to compensate for and restore lost functions. These compensatory/restorative properties are explained by an abundant synaptic plasticity and the convergence of multimodal central and peripheral signals. In addition, extra-cerebellar structures contribute also to the recovery after a cerebellar injury. Clinically, some patients show remarkable improvement of severe ataxic symptoms associated with trauma, stroke, metabolism, or immune-mediated cerebellar ataxia (IMCA, e.g., multiple sclerosis, paraneoplastic cerebellar degeneration, gluten ataxia, anti-GAD65 antibody-associated cerebellar ataxia). However, extension of a cerebellar lesion can impact upon the fourth ventricle or the brainstem, either by direct or indirect mechanisms, leading to serious complications. Moreover, cerebellar reserve itself is affected by advanced cell loss and, at some point of disease progression, deficits become irreversible. Such phase transition from a treatable/restorable state (the reserve is still sufficient) to an untreatable state (the reserve is severely affected) is a loss of therapeutic opportunity, highlighting the need for early treatment during the restorable stage. Based on the motto of “Time is Brain,” a warning that stresses the importance of early therapeutic intervention in ischemic diseases, we propose “Time is Cerebellum” as a principle in the management of patients with cerebellar diseases, especially immune ataxias whose complexity often delay the therapeutic intervention. Indeed, this concept should not be restricted to ischemic cerebellar diseases. We argue that every effort should be made to reduce the diagnostic delay and to initiate early therapy to avoid the risk of transition from a treatable state to an irreversible condition and an associated accumulation of disability. The myriad of disorders affecting the cerebellum is a challenging factor that may contribute to irreversible disability if the window of therapeutic opportunity is missed. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) are short noncoding RNAs of 19-25 nucleotides in length that regulate gene expression at the post-transcriptional level. Dysregulation of miRNAs is associated with many disorders and neurodegenerative diseases affecting numerous different pathways and processes, of which many have not yet been completely explored. Recent studies even indicate a crucial role of miRNAs during brain development, with differential expression patterns of several miRNAs seen in both developing and mature cells. A miRNA profiling in brain tissue and the fundamental understanding of their effects might optimize the therapeutical treatment of various neurological disorders. In this study, we performed miRNA array analysis of enriched cerebellar Purkinje cell (PC) samples from both young and mature rat cerebella. We used laser microdissection (LMD) to enrich PC for a highly specific miRNA profiling. Altogether, we present the expression profile of at least 27 miRNAs expressed in rat cerebellar PC and disclose a different expression pattern of at least three of these miRNAs during development. These miRNAs are potential candidates for the regulation and control of cerebellar PC development, including neuritic and dendritic outgrowth as well as spine formation. [ABSTRACT FROM AUTHOR]

Neural representations of limb movement kinematic parameters are common among central nervous system structures involved in motor control, such as the interpositus nucleus of the cerebellum. Much experimental evidence indicates that neurons in the interpositus may encode limb kinematic parameters both during active, voluntary actions and during limb motion imposed passively, which entrains only sensory afferents. With respect to the sensory processing of information related to movement kinematics, we show that interpositus neuronal activity can parse out the directional from the scalar component (i.e., the movement speed) of the velocity vector. Moreover, a differential role for the anterior and posterior portion of interpositus in encoding these parameters emerged from these data, since the activity of the posterior interpositus was specifically associated to changes of movement speed. Limb movement representations in the interpositus nucleus may be instrumental for the control of goal-directed movements such as shaping hand during grasping or precise foot placement during gait. Finally, we discuss the idea that sensory information about the movement kinematics contribute to both feedback and anticipatory processes for limb movement control. [ABSTRACT FROM AUTHOR]

An exciting hypothesis about the cerebellum is that its role is one of state estimation—a process that combines efferent copies of motor commands with afferent sensory signals to produce a representation of the current status of the peripheral motor system. Sensory inputs alone cannot provide a perfect state signal because of inevitable delays in their afferent pathways. We have recently reported the effects of transcranial magnetic stimulation (TMS) over the ipsilateral cerebellum as healthy subjects made rapid reaching movements towards visually defined targets (Miall et al. in PLoS Biology 5:2733–2744, ). Errors in the initial direction and in the final finger position of this reach-to-target movement were consistent with the reaching movements being planned and initiated from an estimated hand position that was about 138 ms out of date. This interval is consistent with estimates of the delays in sensory motor pathways that would inform the central nervous system of the peripheral status. We now report new data using the same paradigm, testing the effects of varying the TMS stimulus train from one, two, or three pulses. We show that the errors in movement are relatively insensitive to the TMS pulse-train duration. The estimated time interval by which the hand position is mislocalized varied by only 12 ms as the TMS train duration increased by 100 ms. Thus, this interval is likely to reflect physiological processes within the cerebellum rather than the TMS-stimulus duration. This new evidence supports our earlier claim that the cerebellum is responsible for predictively updating a central state estimate over an interval of about 120–140 ms. Dysfunction of the cerebellum, whether through disease or experimental procedures, leads to motor errors consistent with a loss of knowledge of the true state of the motor system. [ABSTRACT FROM AUTHOR]

The cerebellum is a key-actor in motor control. Attempting to extract the motor codes underlying the organization of movement and the rules of signal processing applied by the cerebellar modules has been and remains a major goal for many researchers worldwide. There is an impressive body of evidence showing that the cerebellar pathways influence basic aspects of movement control including: anticipation, timing of motor commands, sensorimotor synchronization, sensorimotor associations and tuning of the magnitudes of muscle activities. The cerebellum contains more neurons than any other part of the brain and is considered as an extremely powerful machine for deciphering information. In this issue, we have gathered scientists working on the field of motor control to provide an overview of recent advances in our understanding of the contribution of this remarkable circuitry in the elaboration and shaping of motor commands. [ABSTRACT FROM AUTHOR]

Besides its known importance for motor coordination, the cerebellum plays a major role in associative learning. The form of cerebellum-dependent associative learning, which has been examined in greatest detail, is classical conditioning of eyeblink responses. The much advanced knowledge of anatomical correlates, as well as cellular and molecular mechanisms involved in eyeblink conditioning in animal models are of particular importance because there is general acceptance that findings in humans parallel the animal data. The aim of the present review is to give an update of findings in humans. Emphasis is put on human lesion studies, which take advantage of the advances of high-resolution structural magnetic resonance imaging (MRI). In addition, findings of functional brain imaging in healthy human subjects are reviewed. The former helped to localize areas involved in eyeblink conditioning within the cerebellum, the latter was in particular helpful in delineating extracerebellar neural substrates, which may contribute to eyeblink conditioning. Human lesion studies support the importance of cortical areas of the ipsilateral superior cerebellum both in the acquisition and timing of conditioned eyeblink responses (CR). Furthermore, the ipsilateral cerebellar cortex seems to be also important in extinction of CRs. Cortical areas, which are important for CR acquisition, overlap with areas related to the control of the unconditioned eyeblink response. Likewise, cortical lesions are followed by increased amplitudes of unconditioned eyeblinks. These findings are in good accordance with the animal literature. Knowledge about contributions of the cerebellar nuclei in humans, however, is sparse. Due to methodological limitations both of human lesion and functional MRI studies, at present no clear conclusions can be drawn on the relative contributions of the cerebellar cortex and nuclei. [ABSTRACT FROM AUTHOR]

In the adult central nervous system (CNS), γ‐amino butyric acid (GABA) is a predominant inhibitory neurotransmitter, and is involved in the expression of various higher brain functions. In the cerebellum, formation of GABAergic synapses is crucial for cerebellar functions. However, it is not fully understood how GABAergic synapses and networks are formed. We are morphologically investigating the developmental changes in GABAergic signaling and the mechanisms underlying the assembly of GABAergic synapses using the cerebellum, which provides an ideal system for the investigation of brain development. The anatomy and development of GABAergic synapses and networks in the cerebellar cortex are reviewed, the key factors for the formation of GABAergic synapses are addressed, and the mechanisms underlying the formation of cerebellar GABAergic networks are discussed. [ABSTRACT FROM AUTHOR]

The somatotopical organization of the climbing fiber input to the paravermal region of lobulus simplex (LS, lobule VIa) was charted in the cerebellar cortex of anaesthetized rats. From medial to lateral in LS, zones a 2 , c 1 , c 2 and c 3 were identified. Forelimb responses were found in both LS and the paramedian lobule (PML) and simultaneous recordings from the c 1 zone in both lobules showed that trial-by-trial fluctuations in climbing fiber field size evoked by ipsilateral forelimb stimulation did not occur in synchrony, suggesting that the two parts of the same zone are not closely linked by their climbing fiber input. Electrophysiological mapping in combination with a double fluorescent axonal tracing strategy (mix of Fluoro-Emerald and green beads, and mix of Fluoro-Ruby and red beads) revealed that the two parts of the c 1 zone receive climbing fiber input from similar territories in the medial and dorsal accessory olives, but that only 4% of the total population of labelled cells have axons that branch to supply climbing fiber afferents to both regions of cortex. The corticonuclear output of the two parts of the zone was found in mainly overlapping regions of the transitional region between the anterior and posterior divisions of nucleus interpositus. Overall, the results suggest that the olivocerebellar and corticonuclear projections of cerebellar zones are similarly organized in rat and cat, implying that the function of individual zones is conserved between species. [ABSTRACT FROM AUTHOR]

Recent studies have established the existence of an innate immune system in the central nervous system (CNS) and implicated a critical role for this system in both normal and pathological processes. Astrocytes and microglia, normal components of the CNS, are the primary cell types that comprise the innate immune system of the CNS. Basic to their role during normal and adverse conditions is the production of neuroimmune factors such as cytokines and chemokines, which are signaling molecules that initiate or coordinate downstream cellular actions. During adverse conditions, cytokines and chemokines function in defensive and repair. However, if expression of these factors becomes dysregulated, abnormal CNS function can result. Both neurons and glial cells of the CNS express receptors for cytokines and chemokines, but the biological consequence of receptor activation has yet to be fully resolved. Our studies show that neuroadaptive changes are produced in primary cultures of rat cerebellar cells chronically treated with the cytokine interleukin-6 (IL-6) and in the cerebellum of transgenic mice that chronically express elevated levels of IL-6 in the CNS. In the cerebellum in culture and in vivo, the neuroadaptive changes included alterations in the level of expression of proteins involved in gene expression, signal transduction, and synaptic transmission. Associated with these changes were alterations in neuronal function. A comparison of results from the cultured cerebellar cells and cerebellum of the transgenic mice indicated that the effects of IL-6 can vary across neuronal types. However, alterations in mechanisms involved in Ca homeostasis were observed in all cell types studied. These results indicate that modifications in cerebellar function are likely to occur in disorders associated with elevated levels of IL-6 in the cerebellum. [ABSTRACT FROM AUTHOR]

To understand the function of cerebellar granule cells, we need detailed knowledge about the information carried by their afferent mossy fibers and how this information is integrated by the granule cells. Recently, we made whole cell recordings from granule cells in the non-anesthetized, decerebrate cats. All recordings were made in the forelimb area of the C3 zone for which the afferent and efferent connections and functional organization have been investigated in detail. Major findings of the study were that the mossy fiber input to single granule cells was modality- and receptive field-specific and that simultaneous activity in two and usually more of the afferent mossy fibers were required to activate the granule cell spike. The high threshold for action potentials and the convergence of afferents with virtually identical information suggest that an important function of granule cells is to increase the signal-to-noise ratio of the mossy fiber–parallel fiber information. Thus a high-sensitivity, noisy mossy fiber input is transformed by the granule cell to a high-sensitivity, low-noise signal. [ABSTRACT FROM AUTHOR]