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The aim of this consensus paper is to discuss the roles of the cerebellum in human gait, as well as its assessment and therapy. Cerebellar vermis is critical for postural control. The cerebellum ensures the mapping of sensory information into temporally relevant motor commands. Mental imagery of gait involves intrinsically connected fronto-parietal networks comprising the cerebellum. Muscular activities in cerebellar patients show impaired timing of discharges, affecting the patterning of the synergies subserving locomotion. Ataxia of stance/gait is amongst the first cerebellar deficits in cerebellar disorders such as degenerative ataxias and is a disabling symptom with a high risk of falls. Prolonged discharges and increased muscle coactivation may be related to compensatory mechanisms and enhanced body sway, respectively. Essential tremor is frequently associated with mild gait ataxia. There is growing evidence for an important role of the cerebellar cortex in the pathogenesis of essential tremor. In multiple sclerosis, balance and gait are affected due to cerebellar and spinal cord involvement, as a result of disseminated demyelination and neurodegeneration impairing proprioception. In orthostatic tremor, patients often show mild-to-moderate limb and gait ataxia. The tremor generator is likely located in the posterior fossa. Tandem gait is impaired in the early stages of cerebellar disorders and may be particularly useful in the evaluation of pre-ataxic stages of progressive ataxias. Impaired inter-joint coordination and enhanced variability of gait temporal and kinetic parameters can be grasped by wearable devices such as accelerometers. Kinect is a promising low cost technology to obtain reliable measurements and remote assessments of gait. Deep learning methods are being developed in order to help clinicians in the diagnosis and decision-making process. Locomotor adaptation is impaired in cerebellar patients. Coordinative training aims to improve the coordinative strategy and foot placements across strides, cerebellar patients benefiting from intense rehabilitation therapies. Robotic training is a promising approach to complement conventional rehabilitation and neuromodulation of the cerebellum. Wearable dynamic orthoses represent a potential aid to assist gait. The panel of experts agree that the understanding of the cerebellar contribution to gait control will lead to a better management of cerebellar ataxias in general and will likely contribute to use gait parameters as robust biomarkers of future clinical trials.

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.

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.

The functional neuroanatomy of cerebellar systems has been extensively studied during the past decades by means of experimental animal studies, anatomoclinical studies, as well as structural and functional neuroimaging studies in patients and healthy subjects. Within a system of closed-loop circuits, this wealth of studies identified reciprocal projections between the cerebellar structures and the supratentorial areas subserving sensorimotor, cognitive, and affective function. It has been shown that cerebellar output is mediated by the deep cerebellar nuclei, mainly by the dentate nucleus (DN), which project to the supratentorial cortex via the thalamus (cerebello-thalamo-cortical pathway). In turn, the cortical areas that are the target of cerebellar output project back to the cerebellum via the pons (cortico-ponto-cerebellar pathway). Regions of the cerebellar cortex that receive input from a specific supratentorial area, are the same regions that project back to that supratentorial area, thus forming closed-loop circuits. These projections are largely crossed, connecting the cerebral hemispheres primarily with the contralateral cerebellar hemispheres.

Cerebellar and afferent ataxias present with a characteristic gait disorder that reflects cerebellar motor dysfunction and sensory loss. These disorders are a diagnostic challenge for clinicians because of the large number of acquired and inherited diseases that cause cerebellar and sensory neuron damage. Among such conditions that are recessively inherited, Friedreich ataxia and RFC1-associated cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) include the characteristic clinical, neuropathological and imaging features of ganglionopathies, a distinctive non-length-dependent type of sensory involvement. In this Review, we discuss the typical and atypical phenotypes of Friedreich ataxia and CANVAS, along with the features of other recessive ataxias that present with a ganglionopathy or polyneuropathy, with an emphasis on recently described clinical features, natural history and genotype-phenotype correlations. We review the main developments in understanding the complex pathology that affects the sensory neurons and cerebellum, which seem to be most vulnerable to disorders that affect mitochondrial function and DNA repair mechanisms. Finally, we discuss disease-modifying therapeutic advances in Friedreich ataxia, highlighting the most promising candidate molecules and lessons learned from previous clinical trials.

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.”

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-Sequard, of distinguishing between phenomena due to loss of function and those due to irritation as a central principle that should guide any physiological research.

OBJECTIVES To compare the effects of Narrow band CE-Chirps (NB CE-Chirps) and tone bursts (TBs) at 500 Hz and 1000 Hz on the amplitudes and latencies in cervical vestibular evoked myogenic potentials (cVEMPs). DESIGN Thirty-one healthy adult volunteers of varying ages were tested by air conduction at 95 dB nHL. Recording conditions were randomized for each participant and each modality was tested twice. RESULTS NB CE-Chirps showed larger corrected amplitudes than TBs at 500 Hz (p < 0.001) which were themselves larger than NB CE-Chirps and TBs at 1000 Hz (p < 0.001). In older volunteers, NB CE-Chirps 500 and 1000 Hz had significantly higher response rates than TBs 500 Hz (p = 0.039). A negative correlation was observed between the corrected amplitudes and the age of the participants regardless of the stimulus and the frequency studied. The p13 and n23 latencies were not correlated with the age of the subjects. CONCLUSIONS NB CE-Chirps at 500 Hz improved the corrected amplitudes of waveforms in cVEMPs as a result of a better frequency specificity compared with TBs. In the elderly, eliciting cVEMPs at a frequency of 1000 Hz might not be necessary to improve response rates with NB CE-Chirps. Additional studies including a higher number of healthy participants and patients with vestibular disorders are required to confirm these observations.

Movement disorders including chorea, dystonia, tics, myoclonus, and parkinsonism are among the multiple acute and long-term complications of substance use disorders (SUD), including amphetamines, cathinones (“bath salts”), cocaine, opioids. Although not frequently reported, they might significantly affect the lives of people with SUD. For instance, chorea, tics, and stereotypies are hyperkinetic movements reported in people taking amphetamines. Symptoms usually manifest within the first hours of drug use, subsiding thereafter. In some patients, however, movement disorders can have a chronic course, persisting even after the end of amphetamine misuse. This chapter reports the diversity of movement disorders in SUD and their clinical implications, focusing on the manifestations outside the intoxication phase.

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.

The importance of the cerebellum in basic as well as higher order domains of affect processing in the brain has been vividly elaborated and specified by the contributions collected in this book. Indeed, according to increasingly precise research findings in functional neuroimaging and functional neurophysiology, individually delineable areas of the cerebellum play a role in virtually all process levels of the responsible networks of emotion perception, attribution, and experience via a variety of reciprocal connections to the limbic system and distinct areas of the parietal, temporal, and prefrontal cortex. The works in this book identify alternative perspectives in neuroscience research that offer new directions in future investigations. Important aspects will be to pin down the precise cerebellar processes in multiple sensory integration and allocation in cognitive and affective evaluation, and also cognitive-affective as well as motor behavioral responses. In this context, imaging and electrophysiological techniques will highlight the spatial and temporal, and thus the topographic and topological, specificities of the cerebellar areas to the respective networks. In the final chapter, questions and suggestions for future neuroscientific investigations are identified, from whose developments several fields of neurological and psychological disciplines could benefit in order to open up therapeutic avenues for people with cerebellar disorders.

The cerebellum is well known for its contribution to motor performance, but less for its involvement to cognitive and affective processing. The growing interest of clinical and neuroscientific research has resulted in a fascinating focus on the cerebellar mechanisms of emotion. Advances in functional neuroimaging and noninvasive stimulation protocols have successively delineated circumscribed cerebellar areas with its functional and topographic connections to the conventionally predominating cerebral cortex in basic as well as high order emotion processing. This encompasses all information processing stages which include perception and attention, and the evaluation and integration of emotion cues to the trajectories in motor, cognitive, and affective behavior. Not surprisingly, research has identified the cerebellum being part of the brain's network associated with art, morality, and social cognition. This book will provide an overview of the details of these intriguing issues, supporting a contemporary understanding of the fundamental as well as specific features of cerebellar functions within emotion processes.

More and more research has focused on the role of the cerebellum in emotions and social cognition. Structural cerebellar and cerebello-cerebral connectivity abnormalities have been identified in several prevalent neuropsychiatric conditions, which have in some cases even been linked to the severity of the emotional disorder.Non-invasive brain stimulation (NIBS) techniques are currently used to modulate neuronal excitability and tune the connectivity within and between neuronal networks. Targeting the cerebellum with NIBS in order to improve emotions and social behavior in neuropsychiatric conditions seems to be a very interesting and innovative approach. Several studies have already explored the effect of cerebellar vermis stimulation in patients with schizophrenia with promising results. Other neuropsychiatric disorders such as bipolar disorder (BD), obsessive-compulsive disorder (OCD), major depressive disorder, or generalized anxiety disorder (GAD) have received less attention with respect to cerebellar stimulation, although the cerebellum has been implicated in these disorders. We will address NIBS and neuropsychiatric disorders in this chapter. Future research should focus on combining cerebellar NIBS with neuroimaging to unravel the specific role of the cerebellum in emotional disorders. Such studies will be very valuable in establishing causal relationships between the structural and functional abnormalities that can be observed in these disorders, and in the search for neurophysiological biomarkers for emotions. However, it is still unclear which stimulation parameters are optimal. Moreover, an important factor to consider when applying cerebellar NIBS in order to improve emotional or other functioning is cerebellar reserve. Although the cerebellum has a wide variety of plasticity mechanisms and its structural organization intrinsically incorporates a lot of redundancy, this redundancy can be depleted. A certain amount of cerebellar reserve should be preserved to successfully apply NIBS.Systematic studies are therefore needed to clarify the optimal stimulation parameters, and methods should be developed to quantify cerebellar reserve in order to estimate the possible added value of NIBS in the rehabilitation of emotions.

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.

Eye movements are fundamental diagnostic and progression markers of various neurological diseases, including those affecting the cerebellum. Despite the high prevalence of abnormal eye movements in patients with cerebellar disorders, the traditional rating scales do not focus on abnormal eye movements. We formed a consortium of neurologists focusing on cerebellar disorders. The consortium aimed to design and validate a novel Scale for Ocular motor Disorders in Ataxia (SODA). The primary purpose of the scale is to determine the extent of ocular motor deficits due to various phenomenologies. A higher score on the scale would suggest a broader range of eye movement deficits. The scale was designed such that it is easy to implement by non-specialized neurological care providers. The scale was not designed to measure each ocular motor dysfunction's severity objectively. Our validation studies revealed that the scale reliably measured the extent of saccade abnormalities and nystagmus. We found a lack of correlation between the total SODA score and the total International Cooperative Ataxia Rating Scale (ICARS), Scale for Assessment and Rating of Ataxia (SARA), or Brief Ataxia Rating Scale (BARS). One explanation is that conventionally reported scales are not dedicated to eye movement disorders; and when present, the measure of ocular motor function is only one subsection of the ataxia rating scales. It is also possible that the severity of ataxias does not correlate with eye movement abnormalities. Nevertheless, the SODA met the consortium's primary goal: to prepare a simple outcome measure that can identify ocular motor dysfunction in patients with cerebellar ataxia.

Essential tremor (ET) represents one of the commonest movement disorder worldwide and is the most common tremor disorder. ET manifests with various combinations of motor and nonmotor symptoms. The clinical hallmark is a kinetic tremor of upper limbs. Historically, the pathogenesis of ET has been based on the hypothesis of an overactivity of the inferior olive (inferior olive hypothesis: IOH) where the inferior olive would act as the central pace-maker of ET, resulting in impaired electrophysiological discharges of the olivo-cerebellar tract. The absence of structural alterations in post-mortem studies of the inferior olive is a striking argument against the IOH. Furthermore, neuroimaging studies point towards the implication of the cerebello-thalamo-cerebral pathway rather than the IO, and the harmaline model which has been considered as an animal model of ET presents important weaknesses. By contrast, a series of experiments by Louis et al. have provided convincing evidence of impaired wiring of the Purkinje cell microcircuitry and progressive neurodegeneration of the cerebellar cortex. The Purkinje neuron appears as the primary culprit (Purkinjopathy). The cerebellar cortex hypothesis (CCH) has solid neuropathological signatures, unlike the purely physiological IOH. Rather than a dysregulatory electrophysiological disorder suggested by IOH, ET is a clinical-pathological entity similar to late onset neurodegenerative disorders such as Parkinson's disease or Alzheimer's disease. The CCH emphasizes the need to develop novel therapeutic strategies in order to maintain or promote the cerebellar reserve. The modern reconceptualization of ET in a genuine cerebellar disorder is cleaning the IOH to the light of histopathological studies. ET falls in the large basket of the neurodegenerative diseases and we have entered into a novel formulation of the disease pathogenesis with direct impacts on future therapies.

Background and ObjectivesThere is no report on the long-term outcomes of ataxia with antibodies against Delta and Notch-like epidermal growth factor–related (DNER). We aimed to describe the clinical-immunologic features and long-term outcomes of patients with anti-DNER antibodies.MethodsPatients tested positive for anti-DNER antibodies between 2000 and 2020 were identified retrospectively. In those with available samples, immunoglobulin G (IgG) subclass analysis, longitudinal cerebellum volumetry, human leukocyte antigen isotyping, and CSF proteomic analysis were performed. Rodent brain membrane fractionation and organotypic cerebellar slices were used to study DNER cell-surface expression and human IgG binding to the Purkinje cell surface.ResultsTwenty-eight patients were included (median age, 52 years, range 19–81): 23 of 28 (82.1%) were male and 23 of 28 (82.1%) had a hematologic malignancy. Most patients (27/28, 96.4%) had cerebellar ataxia; 16 of 28 (57.1%) had noncerebellar symptoms (cognitive impairment, neuropathy, and/or seizures), and 27 of 28 (96.4%) became moderately to severely disabled. Half of the patients (50%) improved, and 32.1% (9/28) had no or slight disability at the last visit (median, 26 months; range, 3–238). Good outcome significantly associated with younger age, milder clinical presentations, and less decrease of cerebellar gray matter volumes at follow-up. No human leukocyte antigen association was identified. Inflammation-related proteins were overexpressed in the patients' CSF. In the rodent brain, DNER was enriched in plasma membrane fractions. Patients' anti-DNER antibodies were predominantly IgG1/3 and bound live Purkinje cells in vitro.DiscussionDNER ataxia is a treatable condition in which nearly a third of patients have a favorable outcome. DNER antibodies bind to the surface of Purkinje cells and are therefore potentially pathogenic, supporting the use of B-cell–targeting treatments.