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Immune-mediated cerebellar ataxias (IMCAs) have diverse etiologies. Patients with IMCAs develop cerebellar symptoms, characterized mainly by gait ataxia, showing an acute or subacute clinical course. We present a novel concept of latent autoimmune cerebellar ataxia (LACA), analogous to latent autoimmune diabetes in adults (LADA). LADA is a slowly progressive form of autoimmune diabetes where patients are often initially diagnosed with type 2 diabetes. The sole biomarker (serum anti-GAD antibody) is not always present or can fluctuate. However, the disease progresses to pancreatic beta-cell failure and insulin dependency within about 5 years. Due to the unclear autoimmune profile, clinicians often struggle to reach an early diagnosis during the period when insulin production is not severely compromised. LACA is also characterized by a slowly progressive course, lack of obvious autoimmune background, and difficulties in reaching a diagnosis in the absence of clear markers for IMCAs. The authors discuss two aspects of LACA: (1) the not manifestly evident autoimmunity and (2) the prodromal stage of IMCA's characterized by a period of partial neuronal dysfunction where non-specific symptoms may occur. In order to achieve an early intervention and prevent cell death in the cerebellum, identification of the time-window before irreversible neuronal loss is critical. LACA occurs during this time-window when possible preservation of neural plasticity exists. Efforts should be devoted to the early identification of biological, neurophysiological, neuropsychological, morphological (brain morphometry), and multimodal biomarkers allowing early diagnosis and therapeutic intervention and to avoid irreversible neuronal loss. [ABSTRACT FROM AUTHOR]

The present Cerebellar Classic highlights the experimental work of the Swedish neurophysiologist Olov Oscarsson (1931–1996) on the afferent innervation of the cerebellum by axons emanating from neurons in the spinal cord and the inferior olive. Historically, the schemes of cerebellar division had been principally based on the external morphology of lobules and fissures. However, the macroscopic anatomical division of the cerebellum does not coincide with its pattern of functional organization. By defining a system of longitudinal somatotopy, Oscarsson contributed to the much needed plan of cerebellar division that correlates experimental information on axonal connections with physiology. His contribution has ultimately led to the currently accepted microzonal modular scheme of cerebellar corticonuclear microcomplexes. [ABSTRACT FROM AUTHOR]

This Cerebellar Classic highlights the landmark discovery of the innervation of the cerebellar cortex and cerebellar nuclei by noradrenergic and serotoninergic axons emanating, respectively, from the locus coeruleus and the raphé nuclei. Since then, modulation of the activity of cerebellar neurons by the monoamine systems has been studied extensively, as well as their reorganization and modifications during development, plasticity, and disease. The discovery of noradrenergic and serotoninergic innervation of the cerebellum has been a crucial step in understanding the neurochemical relationships between brainstem nuclei and the cerebellum, and the attempts to treat cerebellar ataxias pharmacologically. The large neurochemical repertoire of the cerebellum represents one of the complexities and challenges in the modern appraisal of cerebellar disorders. [ABSTRACT FROM AUTHOR]

The present Cerebellar Classic highlights a paper published in 1908 by the American pathologist Simeon Burt Wolbach (1880–1954), in which he reported multiple hernias of the cerebellum for the first time in 9 cases of increased intracranial pressure. The importance of the meninges and the anatomy of involved compartments is emphasized. [ABSTRACT FROM AUTHOR]

Graph Graph Graph Graph Graph Graph Graph Graph Graph Graph Graph Graph Graph Graph Graph Graph Graph Graph Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Keywords: Cerebellum; Oculomotor; Dysmetria; Flutter; Opsoclonus; Fixation; Nystagmus EN Cerebellum Oculomotor Dysmetria Flutter Opsoclonus Fixation Nystagmus 506 526 21 08/17/23 20230801 NES 230801 From the clinical standpoint, the stratification of cerebellar deficits has evolved since the first reports about 250 years ago. Lesions of the flocculus/paraflocculus cause a gaze-evoked nystagmus, a rebound nystagmus, a down-beat nystagmus, a saccadic pursuit with catch-up saccades, and abnormal VOR/optokinetic responses. Lesions of the nodulus/uvula are associated with a periodic alternating nystagmus, a positional downbeat nystagmus, a head-shaking nystagmus, or an alternating skew deviation. [Extracted from the article]

Paraneoplastic cerebellopathies are immune-mediated disorders targeting primarily the cerebellar circuitry, often presenting in a subacute course. The syndrome often develops before the cancer. Therefore, its identification often leads secondarily to a diagnosis of cancer, a critical step to stabilize symptoms. Two categories of antibodies have been identified these last 30 years: (a) onconeuronal antibodies which are directed against intracellular antigens, and (b) antibodies which are directed against synaptic and cell surface proteins. These latter impact on the location and function of the antigens, causing a genuine neuronal dysfunction. Appropriate and fast tumor screening has emerged as a recommendation facing a subacute cerebellar syndrome suspected to be paraneoplastic. Search for antibodies is now a milestone for the diagnosis. [ABSTRACT FROM AUTHOR]

The internist Hermann Nothnagel (1841–1905) took a special interest in the cerebellum. In an early experimental study on rabbits conducted in 1876, he demonstrated the involvement of the vermis in the pathophysiology of motor ataxia. Between 1879 and 1889, he reported four cases of tectal tumors that clinically manifested with bilateral ophthalmoplegia and unilateral gait ataxia, culminating in the Cerebellar Classic highlighted here. Nothnagel attributed this clinical syndrome to lesions of the colliculi ("quadrigeminal bodies") and compression of the nuclei of the third cranial nerves, but also left open the possibility of the involvement of neighboring structures, such as the cerebellar vermis. Today, the ataxic component of Nothnagel syndrome is explained by a dorsal midbrain abnormality of either neoplastic or vascular origin, involving the superior cerebellar peduncles, besides the oculomotor nerves. [ABSTRACT FROM AUTHOR]

The presence of auto-antibodies that target synaptic machinery proteins was documented recently in immune-mediated cerebellar ataxias. The autoantigens include glutamic acid decarboxylase 65 (GAD65), voltage-gated Ca2+ channel (VGCC), metabotropic glutamate receptor type 1 (mGluR1), and glutamate receptor delta (GluRdelta). GAD65 is involved in the synthesis, packaging, and release of GABA, whereas the other three play important roles in the induction of long-term depression (LTD). Thus, the auto-antibodies toward these synaptic molecules likely impair fundamental synaptic machineries involved in unique functions of the cerebellum, potentially leading to the development of cerebellar ataxias (CAs). This concept has been substantiated recently by a series of physiological studies. Anti-GAD65 antibody (Ab) acts on the terminals of inhibitory neurons that suppress GABA release, whereas anti-VGCC, anti-mGluR1, and anti-GluR Abs impair LTD induction. Notably, the mechanisms that link synaptic dysfunction with the manifestations of CAs can be explained by disruption of the "internal models." The latter can be divided into three levels. First, since chained inhibitory neurons shape the output signals through the mechanism of disinhibition/inhibition, impairments of GABA release and LTD distort the conversion process from the "internal model" to the output signals. Second, these antibodies impair the induction of synaptic plasticity, rebound potentiation, and LTD, on Purkinje cells, resulting in loss of restoration and compensation of the distorted "internal models." Finally, the cross-talk between glutamate and microglia/astrocytes could involve a positive feedback loop that accelerates excitotoxicity. This mini-review summarizes the pathophysiological mechanisms and aims to establish the basis of "auto-antibody-induced cerebellar synaptopathies." [ABSTRACT FROM AUTHOR]

The cerebellum is involved in multiple closed-loops circuitry which connect the cerebellar modules with the motor cortex, prefrontal, temporal, and parietal cortical areas, and contribute to motor control, cognitive processes, emotional processing, and behavior. Among them, the cerebello-thalamo-cortical pathway represents the anatomical substratum of cerebellum-motor cortex inhibition (CBI). However, the cerebellum is also connected with basal ganglia by disynaptic pathways, and cerebellar involvement in disorders commonly associated with basal ganglia dysfunction (e.g., Parkinson's disease and dystonia) has been suggested. Lately, cerebellar activity has been targeted by non-invasive brain stimulation (NIBS) techniques including transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) to indirectly affect and tune dysfunctional circuitry in the brain. Although the results are promising, several questions remain still unsolved. Here, a panel of experts from different specialties (neurophysiology, neurology, neurosurgery, neuropsychology) reviews the current results on cerebellar NIBS with the aim to derive the future steps and directions needed. We discuss the effects of TMS in the field of cerebellar neurophysiology, the potentials of cerebellar tDCS, the role of animal models in cerebellar NIBS applications, and the possible application of cerebellar NIBS in motor learning, stroke recovery, speech and language functions, neuropsychiatric and movement disorders. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The article discusses the role of the cerebellum in motor control and the effects of cerebellar stimulation on the motor cortex. It explains that the cerebellum receives sensory inputs from the spinal cord and integrates them to fine-tune motor activity. The article also highlights the use of various neurophysiological tools, such as electric and magnetic stimulation, to study the inhibitory influence of the cerebellum on the motor cortex. The authors present a study that used functional near-infrared spectroscopy (fNIRS) to measure the effects of cerebellar transcranial direct current stimulation (tDCS) on hemodynamic responses in the motor cortex. The study found that anodal tDCS decreased oxyhemoglobin concentrations in the contralateral motor cortex and increased them in the ipsilateral motor cortex. The article concludes by suggesting that further research is needed to confirm these findings and explore the broader effects of cerebellar stimulation. [Extracted from the article]

Spinocerebellar ataxias (SCAs) represent a large group of hereditary degenerative diseases of the nervous system, in particular the cerebellum, and other systems that manifest with a variety of progressive motor, cognitive, and behavioral deficits with the leading symptom of cerebellar ataxia. SCAs often lead to severe impairments of the patient's functioning, quality of life, and life expectancy. For SCAs, there are no proven effective pharmacotherapies that improve the symptoms or substantially delay disease progress, i.e., disease-modifying therapies. To study SCA pathogenesis and potential therapies, animal models have been widely used and are an essential part of pre-clinical research. They mainly include mice, but also other vertebrates and invertebrates. Each animal model has its strengths and weaknesses arising from model animal species, type of genetic manipulation, and similarity to human diseases. The types of murine and non-murine models of SCAs, their contribution to the investigation of SCA pathogenesis, pathological phenotype, and therapeutic approaches including their advantages and disadvantages are reviewed in this paper. There is a consensus among the panel of experts that (1) animal models represent valuable tools to improve our understanding of SCAs and discover and assess novel therapies for this group of neurological disorders characterized by diverse mechanisms and differential degenerative progressions, (2) thorough phenotypic assessment of individual animal models is required for studies addressing therapeutic approaches, (3) comparative studies are needed to bring pre-clinical research closer to clinical trials, and (4) mouse models complement cellular and invertebrate models which remain limited in terms of clinical translation for complex neurological disorders such as SCAs. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Cerebellum is a key-structure for the modulation of motor, cognitive, social and affective functions, contributing to automatic behaviours through interactions with the cerebral cortex, basal ganglia and spinal cord. The predictive mechanisms used by the cerebellum cover not only sensorimotor functions but also reward-related tasks. Cerebellar circuits appear to encode temporal difference error and reward prediction error. From a chemical standpoint, cerebellar catecholamines modulate the rate of cerebellar-based cognitive learning, and mediate cerebellar contributions during complex behaviours. Reward processing and its associated emotions are tuned by the cerebellum which operates as a controller of adaptive homeostatic processes based on interoceptive and exteroceptive inputs. Lobules VI-VII/areas of the vermis are candidate regions for the cortico-subcortical signaling pathways associated with loss aversion and reward sensitivity, together with other nodes of the limbic circuitry. There is growing evidence that the cerebellum works as a hub of regional dysconnectivity across all mood states and that mental disorders involve the cerebellar circuitry, including mood and addiction disorders, and impaired eating behaviors where the cerebellum might be involved in longer time scales of prediction as compared to motor operations. Cerebellar patients exhibit aberrant social behaviour, showing aberrant impulsivity/compulsivity. The cerebellum is a master-piece of reward mechanisms, together with the striatum, ventral tegmental area (VTA) and prefrontal cortex (PFC). Critically, studies on reward processing reinforce our view that a fundamental role of the cerebellum is to construct internal models, perform predictions on the impact of future behaviour and compare what is predicted and what actually occurs. [ABSTRACT FROM AUTHOR]

This Cerebellar Classic highlights a work by the physician and novelist, Silas Weir Mitchell (1829–1914), a pupil of Claude Bernard and a founding father of American neurology. Published in the aftermath of the American Civil War, the article reported observations on cerebellar physiology based on ablation and tissue freezing experiments in pigeons, rabbits, and guinea pigs. Mitchell communicated his results before the Academy of Natural Sciences of Philadelphia, and proposed a general theory of the cerebellum as an augmenting and reinforcing organ to the cerebrospinal motor system. After reviewing and contrasting previous theories of Flourens and Bouillaud, Mitchell formulated his own theory, which was in line with the views of Rolando and Luys. The theory emphasized the necessity, initially suggested by Brown-Séquard, of distinguishing between phenomena due to loss of function and those due to irritation as a central principle that should guide any physiological research. [ABSTRACT FROM AUTHOR]

Highly contagious pandemic due to novel coronavirus SARS-CoV-2, COVID-19 has significantly affected humankind. At the onset of the pandemic, it was believed that it primarily affects the respiratory and hematological system, and has minimal influence on the human brain, even less so on the cerebellum. It was thought that the effects of a pandemic on cerebellar disorders would be the same as it would affect any other chronic neurological disease. It turned out that our understanding of the effects of COVID-19 on the cerebellar system was premature. Over the last 2 years, we appreciated many diverse and direct effects of COVID-19 on cerebellar function. SARS-CoV-2 affects the cerebellum via direct viral invasion, but even more so through its effects on immune, hematological, and metabolic pathways. Increasing evidence suggested the indirect effects of COVID-19 on preexisting chronic cerebellar disease due to lack of in-person care and social isolation. This editorial concisely summarizes critical literature on COVID-19 and the cerebellum published over the last 2 years. [ABSTRACT FROM AUTHOR]

An integral component of neural ontogeny and plasticity is the ongoing generation of new neurons from precursor cells throughout the lifespan in virtually all animals with a nervous system. In mammals, postnatal neurogenesis has been documented in the cerebellum, olfactory bulb, hippocampus, striatum, substantia nigra, hypothalamus, and amygdala. Germinal centers of new neuron production in the adult brain have been identified in the neuroepithelium of the subventricular zone and the dentate gyrus. One of the earliest lines of evidence gathered came from studies on the production of cerebellar microneurons in the external germinal layer of rodents and carnivores in the 1960s and 1970s. The undeniable pioneer of that research was the insightful developmental neurobiologist Joseph Altman (1925–2016). This Cerebellar Classic is devoted to the groundbreaking work of Altman and his graduate student and, subsequently, fellow faculty member, Gopal Das (1933–1991), on postnatal neurogenesis using tritiated thymidine autoradiography to tag newly formed neurons in the cerebellum of cats. Perseverant to their ideas and patiently working in West Lafayette (Indiana), they were the founders of two fields that brought about paradigm shifts and led to an explosive growth in brain research: adult neurogenesis and neural tissue transplantation. [ABSTRACT FROM AUTHOR]

1 Schematic diagram of the pathophysiological mechanisms underlying anti-VGCC, anti-mGluR1, and anti-GluR delta-associated cerebellar ataxias ("LTDpathies"). Basal synaptic transmission is impaired not only by anti-VGCC Abs but also by anti-mGluR1 and GluR delta Abs [[24]]. These studies suggest that anti-VGCC, anti-mGluR1, and anti-GluR delta Abs-associated cerebellar ataxias share one common pathophysiological mechanism, the deregulated PF-PC LTD. In IMCAs, various synaptic proteins, such as glutamic acid decarboxylase 65 (GAD65), voltage-gated Ca channel (VGCC), metabotropic glutamate receptor type 1 (mGluR1), and glutamate receptor delta (GluR delta), are targets of auto-immunity [[14]-[16]]. [Extracted from the article]

Stroke of the cerebellum represents about 10% of strokes of the brain. Both infarction and hemorrhage manifest with symptoms related to the location and extent of the lesion(s). Bilateral cerebellar infarcts constitute up to one third of all cerebellar infarctions. The leading cause of cerebellar infarcts is emboli of cardiac origin or from intra-arterial sources. Potential complications include brainstem compression and hydrocephalus. Malignant cerebellar edema is a life-threatening complication of ischemic posterior circulation stroke requiring urgent management. The advent of MRI has revolutionized the early diagnosis in vivo, showing small and large territorial infarcts, hemorrhages, and venous infarcts. Endovascular procedures are growingly applied and are impacting on the prognosis of stroke, although cerebellar stroke from occlusion of small cerebellar arteries is currently not accessible to thrombectomy. Surgical procedures of space-occupying stroke include external ventricular drainage, suboccipital craniotomy, or combined procedures. In 1849, Robert Dunn (1799–1877), an English surgeon, reported the details of a case of apoplexy of the cerebellum in a 52-year-old man, pointing to the importance of post-mortem studies of patients followed meticulously during lifetime. Dunn discussed inflammation surrounding hemorrhage as a source of cerebral degeneration, linking for the first time cerebellar stroke, neuroinflammation, and atherosclerosis. [ABSTRACT FROM AUTHOR]

The evolution of the prominent role of the cerebellum in the development of composite tools, and cumulative culture, leading to the rise of Homo sapiens is examined. Following Stout and Hecht's (2017) detailed description of stone-tool making, eight key repetitive involvements of the cerebellum are highlighted. These key cerebellar learning involvements include the following: (1) optimization of cognitive-social control, (2) prediction (3) focus of attention, (4) automaticity of smoothness, appropriateness, and speed of movement and cognition, (5) refined movement and social cognition, (6) learns models of extended practice, (7) learns models of Theory of Mind (ToM) of teachers, (8) is predominant in acquisition of novel behavior and cognition that accrues from the blending of cerebellar models sent to conscious working memory in the cerebral cortex. Within this context, the evolution of generalization and blending of cerebellar internal models toward optimization of social-cognitive learning is described. It is concluded that (1) repetition of movement and social cognition involving the optimization of internal models in the cerebellum during stone-tool making was the key selection factor toward social-cognitive and technological advancement, (2) observational learning during stone-tool making was the basis for both technological and social-cognitive evolution and, through an optimizing positive feedback loop between the cerebellum and cerebral cortex, the development of cumulative culture occurred, and (3) the generalization and blending of cerebellar internal models related to the unconscious forward control of the optimization of imagined future states in working memory was the most important brain adaptation leading to intertwined advances in stone-tool technology, cognitive-social processes behind cumulative culture (including the emergence of language and art) and, thereby, with the rise of Homo sapiens. [ABSTRACT FROM AUTHOR]

The virtual practice has made major advances in the way that we care for patients in the modern era. The culture of virtual practice, consulting, and telemedicine, which had started several years ago, took an accelerated leap as humankind was challenged by the novel coronavirus pandemic (COVID19). The social distancing measures and lockdowns imposed in many countries left medical care providers with limited options in evaluating ambulatory patients, pushing the rapid transition to assessments via virtual platforms. In this novel arena of medical practice, which may form new norms beyond the current pandemic crisis, we found it critical to define guidelines on the recommended practice in neurotology, including remote methods in examining the vestibular and eye movement function. The proposed remote examination methods aim to reliably diagnose acute and subacute diseases of the inner-ear, brainstem, and the cerebellum. A key aim was to triage patients into those requiring urgent emergency room assessment versus non-urgent but expedited outpatient management. Physicians who had expertise in managing patients with vestibular disorders were invited to participate in the taskforce. The focus was on two topics: (1) an adequate eye movement and vestibular examination strategy using virtual platforms and (2) a decision pathway providing guidance about which patient should seek urgent medical care and which patient should have non-urgent but expedited outpatient management. [ABSTRACT FROM AUTHOR]

Using bifocal TMS-EEG, the authors found that conditioning stimulation over cerebellum suppressed the amplitude of early peaks within the M1 TMS evoked EEG potentials (TEPs). The massive reciprocal interconnections between the cerebellum and cerebral cortex link sensorimotor, associative, and limbic regions of the cerebral cortex with the cerebellum in a topographically precise manner via segregated channels [[2]]. Cerebellar cortex exerts a strong inhibitory effect upon cerebellar nuclei, the sole output of the cerebellar circuitry [[1]]. [Extracted from the article]

The traditional view on the cerebellum is that it controls motor behavior. Although recent work has revealed that the cerebellum supports also nonmotor functions such as cognition and affect, only during the last 5 years it has become evident that the cerebellum also plays an important social role. This role is evident in social cognition based on interpreting goal-directed actions through the movements of individuals (social "mirroring") which is very close to its original role in motor learning, as well as in social understanding of other individuals' mental state, such as their intentions, beliefs, past behaviors, future aspirations, and personality traits (social "mentalizing"). Most of this mentalizing role is supported by the posterior cerebellum (e.g., Crus I and II). The most dominant hypothesis is that the cerebellum assists in learning and understanding social action sequences, and so facilitates social cognition by supporting optimal predictions about imminent or future social interaction and cooperation. This consensus paper brings together experts from different fields to discuss recent efforts in understanding the role of the cerebellum in social cognition, and the understanding of social behaviors and mental states by others, its effect on clinical impairments such as cerebellar ataxia and autism spectrum disorder, and how the cerebellum can become a potential target for noninvasive brain stimulation as a therapeutic intervention. We report on the most recent empirical findings and techniques for understanding and manipulating cerebellar circuits in humans. Cerebellar circuitry appears now as a key structure to elucidate social interactions. [ABSTRACT FROM AUTHOR]

The current worldwide severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic that causes coronavirus disease 2019 (COVID-19) has brought some medical systems to the brink of collapse. This crisis is also negatively impacting the care of patients with non-COVID-19 conditions, including those with cerebellar ataxia (CA). Older patients with CA and those with immune-mediated ataxias on immunosuppressive medication are potentially at high risk of developing serious complications of the infection, although it is also possible that immunosuppressive agents may provide a defense against cytokine storm. This has implications for even greater attention to preventing contracting the disease through physical distancing and/or isolation. The CA patient population is also at higher risk because of the neurological complexities of their underlying disorder and the comorbid medical illnesses that often accompany the genetic ataxias. As the disruption of social patterns and healthcare delivery in response to the crisis continues, interruption of rehabilitation, speech and language therapy, and face-to-face consultations threatens to have a negative impact on the course and well-being of CA patients. Mental and physical health is also potentially at greater risk because the prevailing uncertainty and anxiety may be superimposed upon cerebellum-specific neuropsychological challenges. We identify and review some of the short- and long-term consequences of this global pandemic for the community of ataxia patients and their families and for the clinical and academic neurologists/ataxiologists caring for these patients. This includes the recognition that telemedicine has emerged as a principle means of caregiver-patient contact and that neurological manifestations of COVID-19 including those specific to cerebellar neurobiology are increasingly recognized and will require close surveillance and monitoring. This COVID-19 Cerebellum Task Force consensus provides some guidance on how we may approach this uncertain time and consider preparing for the new realities we face in CA patient care once this acute crisis has passed. [ABSTRACT FROM AUTHOR]

Aside from well-characterized immune-mediated ataxias with a clear trigger and/or association with specific neuronal antibodies, a large number of idiopathic ataxias are suspected to be immune mediated but remain undiagnosed due to lack of diagnostic biomarkers. Primary autoimmune cerebellar ataxia (PACA) is the term used to describe this later group. An International Task Force comprising experts in the field of immune ataxias was commissioned by the Society for Research on the Cerebellum and Ataxias (SRCA) in order to devise diagnostic criteria aiming to improve the diagnosis of PACA. The proposed diagnostic criteria for PACA are based on clinical (mode of onset, pattern of cerebellar involvement, presence of other autoimmune diseases), imaging findings (MRI and if available MR spectroscopy showing preferential, but not exclusive involvement of vermis) and laboratory investigations (CSF pleocytosis and/or CSF-restricted IgG oligoclonal bands) parameters. The aim is to enable clinicians to consider PACA when encountering a patient with progressive ataxia and no other diagnosis given that such consideration might have important therapeutic implications. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Sporadically advocated over the last two centuries, a cerebellar role in cognition and affect has been rigorously established in the past few decades. In the clinical domain, such progress is epitomized by the "cerebellar cognitive affective syndrome" ("CCAS") or "Schmahmann syndrome." Introduced in the late 1990s, CCAS reflects a constellation of cerebellar-induced sequelae, comprising deficits in executive function, visuospatial cognition, emotion–affect, and language, over and above speech. The CCAS thus offers excellent grounds to investigate the functional topography of the cerebellum, and, ultimately, illustrate the precise mechanisms by which the cerebellum modulates cognition and affect. The primary objective of this task force paper is thus to stimulate further research in this area. After providing an up-to-date overview of the fundamental findings on cerebellar neurocognition, the paper substantiates the concept of CCAS with recent evidence from different scientific angles, promotes awareness of the CCAS as a clinical entity, and examines our current insight into the therapeutic options available. The paper finally identifies topics of divergence and outstanding questions for further research. [ABSTRACT FROM AUTHOR]

There is currently no accepted classification of autosomal recessive cerebellar ataxias, a group of disorders characterized by important genetic heterogeneity and complex phenotypes. The objective of this task force was to build a consensus on the classification of autosomal recessive ataxias in order to develop a general approach to a patient presenting with ataxia, organize disorders according to clinical presentation, and define this field of research by identifying common pathogenic molecular mechanisms in these disorders. The work of this task force was based on a previously published systematic scoping review of the literature that identified autosomal recessive disorders characterized primarily by cerebellar motor dysfunction and cerebellar degeneration. The task force regrouped 12 international ataxia experts who decided on general orientation and specific issues. We identified 59 disorders that are classified as primary autosomal recessive cerebellar ataxias. For each of these disorders, we present geographical and ethnical specificities along with distinctive clinical and imagery features. These primary recessive ataxias were organized in a clinical and a pathophysiological classification, and we present a general clinical approach to the patient presenting with ataxia. We also identified a list of 48 complex multisystem disorders that are associated with ataxia and should be included in the differential diagnosis of autosomal recessive ataxias. This classification is the result of a consensus among a panel of international experts, and it promotes a unified understanding of autosomal recessive cerebellar disorders for clinicians and researchers. [ABSTRACT FROM AUTHOR]

The cerebellum is best known for its role in controlling motor behaviors. However, recent work supports the view that it also influences non-motor behaviors. The contribution of the cerebellum towards different brain functions is underscored by its involvement in a diverse and increasing number of neurological and neuropsychiatric conditions including ataxia, dystonia, essential tremor, Parkinson's disease (PD), epilepsy, stroke, multiple sclerosis, autism spectrum disorders, dyslexia, attention deficit hyperactivity disorder (ADHD), and schizophrenia. Although there are no cures for these conditions, cerebellar stimulation is quickly gaining attention for symptomatic alleviation, as cerebellar circuitry has arisen as a promising target for invasive and non-invasive neuromodulation. This consensus paper brings together experts from the fields of neurophysiology, neurology, and neurosurgery to discuss recent efforts in using the cerebellum as a therapeutic intervention. We report on the most advanced techniques for manipulating cerebellar circuits in humans and animal models and define key hurdles and questions for moving forward. [ABSTRACT FROM AUTHOR]

Differential ultracentrifugation and subcellular fractionation historically helped to study the components of the cell, to discover new cellular organelles, and to decipher their morphological and molecular properties. In neuroscience, the technique has yielded important results on neuron biochemistry and the mechanisms of synaptic transmission. This Cerebellar Classic is devoted to the pioneering work of Manuel del Cerro, Ray S. Snider, and Mary Lou Oster-Granite, who isolated purified fractions after successive centrifugations of the rat cerebellum from birth to adulthood and studied them under the electron microscope. [ABSTRACT FROM AUTHOR]

The olivocerebellar tract has unique morphological, physiological, and developmental properties. Olivocerebellar axons are the source of multiple climbing fibers (CFs). The synapse between CFs and the Purkinje neuron is one of the most powerful excitatory in the central nervous system. Complex spikes are composed of an initial large amplitude spike followed by spikelets. The spatiotemporal patterns of complex/simple spikes complement the rate coding to enhance the accuracy of motor and cognitive processing, and to improve predictions related to internal models. Understanding the role of complex spikes is essential in clarifying how the cerebellar cortex contributes to learning, motor control, cognitive tasks, and the processing of emotions. This Cerebellar Classic is devoted to the pioneering work of Eccles, Llinás, and Sasaki on complex spikes using intracellular recordings from Purkinje neurons. [ABSTRACT FROM AUTHOR]

108122 7 Waespe W, Cohen B, Raphan T. Role of the flocculus and paraflocculus in optokinetic nystagmus and visual-vestibular interactions: effects of lesions. A decade later, Raphan and Cohen lesioned the macaque cerebellar nodulus and ventral uvula, prolonging the velocity storage time constant [[6]]. A redundant multisensory signal is necessary for accurate motion perception and vestibulo-ocular reflex (VOR). [Extracted from the article]

The thalamus is a neural processor and integrator for the activities of the forebrain. Surprisingly, little is known about the roles of the "cerebellar" thalamus despite the anatomical observation that all the cortico-cerebello-cortical loops make relay in the main subnuclei of the thalamus. The thalamus displays a broad range of electrophysiological responses, such as neuronal spiking, bursting, or oscillatory rhythms, which contribute to precisely shape and to synchronize activities of cortical areas. We emphasize that the cerebellar thalamus deserves a renewal of interest to better understand its specific contributions to the cerebellar motor and associative functions, especially at a time where the anatomy between cerebellum and basal ganglia is being rewritten. [ABSTRACT FROM AUTHOR]

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]

Anti-GAD65 antibodies (anti-GAD65 Abs) are associated with cerebellar ataxia (CA). The significance of anti-GAD65 Abs has been a focus of debates. Since GAD65 is intracellularly located and associated with type 1 diabetes mellitus and different clinical neurological phenotypes such as CA, stiff-person syndrome, and epilepsy, some researchers have argued that anti-GAD65 Abs have no pathogenic roles. On the other hand, recent physiological studies in vitro and in vivo have elucidated that binding of GAD65 by anti-GAD65 Abs elicits loss of GAD65 functions pertaining GABA release with an epitope dependence, leading to the development of CA. Internalization of autoantibodies has been also clarified. These studies provide substantial evidence of the pathogenesis of anti-GAD65 Abs in CA. We also discuss methodological problems in the identification of anti-GAD65 Abs. [ABSTRACT FROM AUTHOR]

Time perception is an essential element of conscious and subconscious experience, coordinating our perception and interaction with the surrounding environment. In recent years, major technological advances in the field of neuroscience have helped foster new insights into the processing of temporal information, including extending our knowledge of the role of the cerebellum as one of the key nodes in the brain for this function. This consensus paper provides a state-of-the-art picture from the experts in the field of the cerebellar research on a variety of crucial issues related to temporal processing, drawing on recent anatomical, neurophysiological, behavioral, and clinical research. The cerebellar granular layer appears especially well-suited for timing operations required to confer millisecond precision for cerebellar computations. This may be most evident in the manner the cerebellum controls the duration of the timing of agonist-antagonist EMG bursts associated with fast goal-directed voluntary movements. In concert with adaptive processes, interactions within the cerebellar cortex are sufficient to support sub-second timing. However, supra-second timing seems to require cortical and basal ganglia networks, perhaps operating in concert with cerebellum. Additionally, sensory information such as an unexpected stimulus can be forwarded to the cerebellum via the climbing fiber system, providing a temporally constrained mechanism to adjust ongoing behavior and modify future processing. Patients with cerebellar disorders exhibit impairments on a range of tasks that require precise timing, and recent evidence suggest that timing problems observed in other neurological conditions such as Parkinson's disease, essential tremor, and dystonia may reflect disrupted interactions between the basal ganglia and cerebellum. The complex concepts emerging from this consensus paper should provide a foundation for further discussion, helping identify basic research questions required to understand how the brain represents and utilizes time, as well as delineating ways in which this knowledge can help improve the lives of those with neurological conditions that disrupt this most elemental sense. The panel of experts agrees that timing control in the brain is a complex concept in whom cerebellar circuitry is deeply involved. The concept of a timing machine has now expanded to clinical disorders. [ABSTRACT FROM AUTHOR]

Non-invasive stimulation of the cerebellum is growingly applied both in the clinic and in research settings to modulate the activities of cerebello-cerebral loops. The anatomical location of the cerebellum, the high responsiveness of the cerebellar cortex to magnetic/electrical stimuli, and the implication of the cerebellum in numerous cerebello-cerebral networks make the cerebellum an ideal target for investigations and therapeutic purposes. In this mini-review, we discuss the potentials of cerebellar neuromodulation in major brain disorders in order to encourage large-scale sham-controlled research and explore this therapeutic aid further. [ABSTRACT FROM AUTHOR]

DBN is the second most common form of nystagmus published according to PubMed citations, gaze-evoked nystagmus being the most common form. A comprehensive single-center study of the large number of patients with vertigo and dizziness revealed that 369 out of 2000 patients were dizzy without having any structural deficits. Among these patients, 24% had central nystagmus; idiopathic DBN was present in 64% of those with central nystagmus [[2]]. Nystagmus is reported in about 84% of spinocerebellar ataxia patients, but DBN is extremely rare and was reported only twice in the literature [[12]]. [Extracted from the article]

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]

The field of non-invasive stimulation of the cerebellum is quickly expanding. The anatomical structure of the cerebellum with a high density of neurons in the superficial layer, its electrical properties, and its participation in numerous closed-loop circuits involved in motor, cognitive, and affective operations both in children and in adults make of the cerebellum a target with very high potential for neuromodulation of both cerebellar and extra-cerebellar disorders, in neurology, psychiatry, and neurosurgery. A common research effort is required to extract the optimal parameters of stimulation and to identify how non-invasive stimulation of the cerebellum modifies cerebellar plasticity and functional connectivity in remote cortical and subcortical areas. A patient stratification should be considered. [ABSTRACT FROM AUTHOR]

Gadolinium (Gd)-based contrast agents (GBCAs) are used in magnetic resonance imaging (MRI) to increase the diagnostic yield. Current reports using animal models or human subjects have shown that GBCAs may be deposited in brain including the cerebellum. Although further studies may be required to clarify the toxicity of GBCAs, we should be more cautious to use these agents particularly in patients who more likely to have repeated enhanced MRI along their lifespan. In this editorial, current studies to clarify the toxicity of GBCAs in the cerebellum are introduced. [ABSTRACT FROM AUTHOR]

Foreign accent syndrome is a rare motor speech disorder that causes patients to speak their language with a non-native accent. In the neurogenic condition, the disorder develops after lesions in the language dominant hemisphere, often affecting Broca's area, the insula, the supplementary motor area and the primary motor cortex. Here, we present two new cases of FAS after posterior fossa lesions. The first case is a 44-year-old, right-handed, Dutch-speaking man who suffered motor speech disturbances and a left hemiplegia after a pontine infarction. Quantified SPECT showed a bilateral hypoperfusion in the inferior lateral prefrontal and medial inferior frontal regions as well as a significant left cerebellar hypoperfusion. Further clinical investigations led to an additional diagnosis of brainstem cognitive affective syndrome which closely relates to Schmahmann's syndrome. The second patient was a 72-year-old right-handed polyglot English man who suffered a stroke in the vascular territory of the left posterior inferior cerebellar artery (PICA) and developed a foreign accent in his mother tongue (English) and in a later learnt language (Dutch). In this paper, we discuss how the occurrence of this peculiar motor speech disorder can be related to a lesion affecting the posterior fossa structures. [ABSTRACT FROM AUTHOR]

Transcranial magnetic and electric stimulation of the brain are novel and highly promising techniques currently employed in both research and clinical practice. Improving or rehabilitating brain functions by modulating excitability with these noninvasive tools is an exciting new area in neuroscience. Since the cerebellum is closely connected with the cerebral regions subserving motor, associative, and affective functions, the cerebello-thalamo-cortical pathways are an interesting target for these new techniques. Targeting the cerebellum represents a novel way to modulate the excitability of remote cortical regions and their functions. This review brings together the studies that have applied cerebellar stimulation, magnetic and electric, and presents an overview of the current knowledge and unsolved issues. Some recommendations for future research are implemented as well. [ABSTRACT FROM AUTHOR]

Essential tremor (ET), clinically characterized by postural and kinetic tremors, predominantly in the upper extremities, originates from pathological activity in the dynamic oscillatory network comprising the majority of nodes in the central motor network. Evidence indicates dysfunction in the thalamus, the olivocerebellar loops, and intermittent cortical engagement. Pathology of the cerebellum, a structure with architecture intrinsically predisposed to oscillatory activity, has also been implicated in ET as shown by clinical, neuroimaging, and pathological studies. Despite electrophysiological studies assessing cerebellar impairment in ET being scarce, their impact is tangible, as summarized in this review. The electromyography-magnetoencephalography combination provided the first direct evidence of pathological alteration in cortico-subcortical communication, with a significant emphasis on the cerebellum. Furthermore, complex electromyography studies showed disruptions in the timing of agonist and antagonist muscle activation, a process generally attributed to the cerebellum. Evidence pointing to cerebellar engagement in ET has also been found in electrooculography measurements, cerebellar repetitive transcranial magnetic stimulation studies, and, indirectly, in complex analyses of the activity of the ventral intermediate thalamic nucleus (an area primarily receiving inputs from the cerebellum), which is also used in the advanced treatment of ET. In summary, further progress in therapy will require comprehensive electrophysiological and physiological analyses to elucidate the precise mechanisms leading to disease symptoms. The cerebellum, as a major node of this dynamic oscillatory network, requires further study to aid this endeavor. [ABSTRACT FROM AUTHOR]

Separating the etiologies of an acute vestibular syndrome (AVS) of central origin is a clinical challenge; the common causes include (1) stroke of the brainstem/cerebellum and (2) demyelinating disorders such as multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD). Overshadowed by the vascular etiologies, the literature describing AVS due to demyelinating disorders has been growing through the last decade. The discovery of IgG-NMO, a specific pathogenic antibody directed against the astrocytic water channel aquaporin-4 (AQP4), has improved the differential diagnoses between MS and NMOSD. AQP4 is particularly expressed in ependymal/subependymal astrocytes and glia limitans astrocyte processes, including around the fourth ventricle. Adding a clinical biomarker to distinguish MS and NMOSD in AVS patients, as reported in this issue, will be of great clinical value. [ABSTRACT FROM AUTHOR]

Essential tremor (ET) is one of the most prevalent neurological disorders in the world. Environmental factors have been implicated in the pathogenesis of ET. In particular, epidemiological studies have suggested that neurotoxic agents, especially β-carboline alkaloids (βCAs), might be generated through Maillard-type reaction. βCAs are molecules which are members of a large group of heterocyclic amines (HCAs, the so-called products of cooking meat). βCAs are highly tremorogenic in animals, producing a marked generalized action tremor soon after systemic administration in a wide range of laboratory animals such as mice, rats and monkeys. Administration of βCAs remains currently the main experimental model of ET. We review the pathogenesis of ET, with a focus on the biochemistry of βCAs, their occurrence and biological activity, their endogenous biosynthesis, their formation in food, their toxicokinetics and their neurotoxicity. We highlight open questions regarding the effects of βCAs in humans. [ABSTRACT FROM AUTHOR]

The cerebellum is involved in sensorimotor operations, cognitive tasks and affective processes. Here, we revisit the concept of the cerebellar syndrome in the light of recent advances in our understanding of cerebellar operations. The key symptoms and signs of cerebellar dysfunction, often grouped under the generic term of ataxia, are discussed. Vertigo, dizziness, and imbalance are associated with lesions of the vestibulo-cerebellar, vestibulo-spinal, or cerebellar ocular motor systems. The cerebellum plays a major role in the online to long-term control of eye movements (control of calibration, reduction of eye instability, maintenance of ocular alignment). Ocular instability, nystagmus, saccadic intrusions, impaired smooth pursuit, impaired vestibulo-ocular reflex (VOR), and ocular misalignment are at the core of oculomotor cerebellar deficits. As a motor speech disorder, ataxic dysarthria is highly suggestive of cerebellar pathology. Regarding motor control of limbs, hypotonia, a- or dysdiadochokinesia, dysmetria, grasping deficits and various tremor phenomenologies are observed in cerebellar disorders to varying degrees. There is clear evidence that the cerebellum participates in force perception and proprioceptive sense during active movements. Gait is staggering with a wide base, and tandem gait is very often impaired in cerebellar disorders. In terms of cognitive and affective operations, impairments are found in executive functions, visual-spatial processing, linguistic function, and affective regulation (Schmahmann's syndrome). Nonmotor linguistic deficits including disruption of articulatory and graphomotor planning, language dynamics, verbal fluency, phonological, and semantic word retrieval, expressive and receptive syntax, and various aspects of reading and writing may be impaired after cerebellar damage. The cerebellum is organized into (a) a primary sensorimotor region in the anterior lobe and adjacent part of lobule VI, (b) a second sensorimotor region in lobule VIII, and (c) cognitive and limbic regions located in the posterior lobe (lobule VI, lobule VIIA which includes crus I and crus II, and lobule VIIB). The limbic cerebellum is mainly represented in the posterior vermis. The cortico-ponto-cerebellar and cerebello-thalamo-cortical loops establish close functional connections between the cerebellum and the supratentorial motor, paralimbic and association cortices, and cerebellar symptoms are associated with a disruption of these loops. [ABSTRACT FROM AUTHOR]