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The impact of ethanol on the fetus is a significant concern as an estimated 2–5% of live births may be affected by prenatal alcohol exposure. This exposure can lead to various functional and structural abnormalities in the cerebral cortex, basal ganglia, diencephalon, and cerebellum, resulting in region-specific symptoms. The deficits relate to the motor and cognitive domains, affecting, in particular, general intelligence, attention, executive functions, language, memory, visual perception, and social skills—collectively called the fetal alcohol spectrum disorder (FASD). Recent studies suggest that damage to the developing cerebellum (in form of alcohol exposure) can impair the cortical targets of the cerebello-thalamo-cortical tract. This malfunction in the cerebello-cerebral loop optimization may be due to disruptions in the formation of the foundational elements of the internal model within the developing cerebellum. Alcohol exposure targets multiple nodes in the reciprocal loops between the cerebellum and cerebral cortex. Here, we examine the possibility that prenatal alcohol exposure damages the developing cerebellum and disrupts the connectivity within the cerebello-cerebral neuronal circuits, exacerbating FASD-related cortical dysfunctions. We propose that malfunctions between cerebellar internal model (critically involved in predictions) and cerebral regions contribute to the deficits observed in FASD. Given the major role of the cerebellum in motor, cognitive, and affective functions, we suggest that therapies should target these malfunctions to mitigate the burden of FASD. We discuss the concept of therapies oriented towards malfunctioning cerebello-cerebral loops (TOMCCLs), emphasizing anti-inflammatory strategies and treatments aimed at modulating cerebellar myelination to restore optimal and predictive cerebello-cerebral functions.

What qualities and abilities are appropriate for a person who plans to become a doctor? To answer this question, it is meaningful to understand the opinions of the general public, since they are important stakeholders in the training of doctors. As part of a national door-to-door questionnaire survey, participants were asked about 16 qualities and abilities they considered suitable for becoming a doctor. Of the 1200 people interviewed, 1190 responded. The ratio of affirmative answers was the highest (92.2%) for the “Accurately judges situations” element, followed by “Cares about others’ feelings” (87.4%), “Understands the reality of medical care and welfare” (87.2%), and “Resistant to mental stress” (86.2%). “High academic ability”, which is currently the most important factor in the actual selection of students, ranked ninth among the sixteen elements (71.8%). Aside from academic ability, the general public places importance on other factors in selecting students for admission to medical schools. This study provides a valuable reference for medical schools regarding admission policies and applicant selection processes.

The clinical category of immune-mediated cerebellar ataxias (IMCAs) is now recognized after 3 decades of clinical and experimental research. The cerebellum gathers about 60% of neurons in the brain, is enriched in numerous plasticity mechanisms, and presents a large variety of antigens at the neuroglial level: ion channels and related proteins, synaptic adhesion/organizing proteins, transmitter receptors, and glial cells. Cerebellar circuitry is especially vulnerable to immune attacks. After the loss of immune tolerance, IMCAs present in an acute or subacute manner with various combinations of a vestibulocerebellar syndrome (VCS), a cerebellar motor syndrome (CMS), and a cerebellar cognitive affective syndrome/Schmahmann’s syndrome (CCAS/SS). IMCAs include gluten ataxia (GA), post-infectious cerebellitis (PIC), Miller Fisher syndrome (MFS), paraneoplastic cerebellar degeneration (PCD), opsoclonus myoclonus syndrome (OMS), anti-glutamic acid decarboxylase (anti-GAD) ataxia, and glial fibrillary acidic protein (GFAP) astrocytopathy (GFAP-A). In addition, multiple sclerosis (MS), acute disseminated encephalomyelitis (ADEM), Behçet disease, and collagen-vascular disorders may also present with cerebellar symptoms when lesions involve cerebellar afferences/efferences. Patients whose clinical profiles do not fit with IMCAs are now gathered in the group of primary autoimmune cerebellar ataxias (PACAs). Latent auto-immune cerebellar ataxia (LACA) refers to a clinical stage with a slow progressive course and a lack of obvious auto-immune background. At a pre-symptomatic stage, patients remain asymptomatic, whereas at the prodromal stage aspecific symptoms occur, announcing the symptomatic neuronal loss. LACA corresponds to a time-window where an intervention could lead to preservation of plasticity mechanisms. Patients may evolve from LACA to PACA and typical IMCAs, highlighting a continuum. Immune ataxias represent a model to elucidate the sequence of events leading to destruction of cerebellar neuronal reserve and develop novel strategies aiming to restore plasticity mechanisms.

The clinical category of immune-mediated cerebellar ataxias (IMCAs) has been established after 3 decades of clinical and experimental research. The cerebellum is particularly enriched in antigens (ion channels and related proteins, synaptic adhesion/organizing proteins, transmitter receptors, glial cells) and is vulnerable to immune attacks. IMCAs include various disorders, including gluten ataxia (GA), post-infectious cerebellitis (PIC), Miller Fisher syndrome (MFS), paraneoplastic cerebellar degeneration (PCD), opsoclonus myoclonus syndrome (OMS), and anti-GAD ataxia. Other disorders such as multiple sclerosis (MS), acute disseminated encephalomyelitis (ADEM), Behçet disease, and collagen vascular disorders may also present with cerebellar symptoms when lesions are localized to cerebellar pathways. The triggers of autoimmunity are established in GA (gluten sensitivity), PIC and MFS (infections), PCD (malignancy), and OMS (infections or malignant tumors). Patients whose clinical profiles do not match those of classic types of IMCAs are now included in the spectrum of primary autoimmune cerebellar ataxia (PACA). Recent remarkable progress has clarified various characteristics of these etiologies and therapeutic strategies in terms of immunotherapies. However, it still remains to be elucidated as to how immune tolerance is broken, leading to autoimmune insults of the cerebellum, and the consecutive sequence of events occurring during cerebellar damage caused by antibody- or cell-mediated mechanisms. Antibodies may specifically target the cerebellar circuitry and impair synaptic mechanisms (synaptopathies). The present Special Issue aims to illuminate what is solved and what is unsolved in clinical practice and the pathophysiology of IMCAs. Immune ataxias now represent a genuine category of immune insults to the central nervous system (CNS).

Cerebellar reserve compensates for and restores functions lost through cerebellar damage. This is a fundamental property of cerebellar circuitry. Clinical studies suggest (1) the involvement of synaptic plasticity in the cerebellar cortex for functional compensation and restoration, and (2) that the integrity of the cerebellar reserve requires the survival and functioning of cerebellar nuclei. On the other hand, recent physiological studies have shown that the internal forward model, embedded within the cerebellum, controls motor accuracy in a predictive fashion, and that maintaining predictive control to achieve accurate motion ultimately promotes learning and compensatory processes. Furthermore, within the proposed framework of the Kalman filter, the current status is transformed into a predictive state in the cerebellar cortex (prediction step), whereas the predictive state and sensory feedback from the periphery are integrated into a filtered state at the cerebellar nuclei (filtering step). Based on the abovementioned clinical and physiological studies, we propose that the cerebellar reserve consists of two elementary mechanisms which are critical for cerebellar functions: the first is involved in updating predictions in the residual or affected cerebellar cortex, while the second acts by adjusting its updated forecasts with the current status in the cerebellar nuclei. Cerebellar cortical lesions would impair predictive behavior, whereas cerebellar nuclear lesions would impact on adjustments of neuronal commands. We postulate that the multiple forms of distributed plasticity at the cerebellar cortex and cerebellar nuclei are the neuronal events which allow the cerebellar reserve to operate in vivo. This cortico-deep cerebellar nuclei loop model attributes two complementary functions as the underpinnings behind cerebellar reserve.

Since the first description of immune-mediated cerebellar ataxias (IMCAs) by Charcot in 1868, several milestones have been reached in our understanding of this group of neurological disorders. IMCAs have diverse etiologies, such as gluten ataxia, postinfectious cerebellitis, paraneoplastic cerebellar degeneration, opsoclonus myoclonus syndrome, anti-GAD ataxia, and primary autoimmune cerebellar ataxia. The cerebellum, a vulnerable autoimmune target of the nervous system, has remarkable capacities (collectively known as the cerebellar reserve, closely linked to plasticity) to compensate and restore function following various pathological insults. Therefore, good prognosis is expected when immune-mediated therapeutic interventions are delivered during early stages when the cerebellar reserve can be preserved. However, some types of IMCAs show poor responses to immunotherapies, even if such therapies are introduced at an early stage. Thus, further research is needed to enhance our understanding of the autoimmune mechanisms underlying IMCAs, as such research could potentially lead to the development of more effective immunotherapies. We underscore the need to pursue the identification of robust biomarkers.

Abstract There is general agreement that auto-antibodies against ion channels and synaptic machinery proteins can induce limbic encephalitis. In immune-mediated cerebellar ataxias (IMCAs), various synaptic proteins, such as GAD65, voltage-gated Ca channel (VGCC), metabotropic glutamate receptor type 1 (mGluR1), and glutamate receptor delta (GluR delta) are auto-immune targets. Among them, the pathophysiological mechanisms underlying anti-VGCC, anti-mGluR1, and anti-GluR delta antibodies remain unclear. Despite divergent auto-immune and clinical profiles, these subtypes show common clinical features of good prognosis with no or mild cerebellar atrophy in non-paraneoplastic syndrome. The favorable prognosis reflects functional cerebellar disorders without neuronal death. Interestingly, these autoantigens are all involved in molecular cascades for induction of long-term depression (LTD) of synaptic transmissions between parallel fibers (PFs) and Purkinje cells (PCs), a crucial mechanism of synaptic plasticity in the cerebellum. We suggest that anti-VGCC, anti-mGluR1, and anti-GluR delta Abs-associated cerebellar ataxias share one common pathophysiological mechanism: a deregulation in PF-PC LTD, which results in impairment of restoration or maintenance of the internal model and triggers cerebellar ataxias. The novel concept of LTDpathies could lead to improvements in clinical management and treatment of cerebellar patients who show these antibodies.

Abstract Background We investigated the gait characteristics of patients with Parkinson’s disease (PD), under free-living conditions, using a wearable device, and assessed their relationships with global cognitive function and motor abnormalities. Methods The study subjects comprised patients with PD aged

Despite concerns raised on the inequality in healthcare provision in Japan, little is known about the factors that hinder candidates' application to medical schools. A nationwide cross-sectional survey was conducted to identify the impact of economic factors and living place on students' choice of and preparation for medical school. The survey was administered to high school teachers with career advisory roles, as they support and likely influence students' choice and decision on this matter. Responses totaling 1,094 were obtained from 1,746 high schools across Japan. The ratio of high schools with two or more students enrolled in medical schools every year is higher in private schools, those with high tuition, and those located in big cities. Approximately 66.8% of the respondents agreed that "It is difficult for students in economically disadvantaged families to enroll in medical schools;" 42.0% agreed that "Some students gave up on aspiring to enter medical schools because they could not afford it," and 61.2% agreed that "Students living in urban areas are more likely to enroll in medical schools." When asked about the percentage of students attending prep school among those aspiring for a medical career, significantly more respondents from private versus public high schools answered "80% or more." When asked about the percentage of parents who are doctors or dentists among students aspiring for a medical career, significantly more respondents from private versus public high schools answered "50% or more." The results suggest that students from lower-income families and those living in rural areas are more likely to be disadvantaged when choosing a medical career (because of financial difficulties) than those who live in urban areas and come from wealthier families. The results imply that economic and geographical divides in medical admission are reflected in high school teachers' perception of and support provided to students.

Background. Freezing of gait (FOG) is an important symptom that can impair activities of daily living in patients with Parkinson’s disease (PD). However, its pathogenic mechanism is largely unknown. The aim of the present study was to elucidate the clinical characteristics of newly diagnosed and levodopa-naïve patients with PD who present with FOG. Methods. A total of 53 patients with untreated PD (29 men and 24 women) within 2 years of disease onset were included in the study. Using item 3 of the Freezing of Gait Questionnaire (FOG-Q), patients were classified as “freezers” and “nonfreezers” and compared for cognitive function, depressive symptoms, apathy, olfactory function, motor severity, gait parameters, and daily physical activity. We also assessed the relationship between FOG severity (total score of items 3–6 on the FOG-Q) and various clinical parameters. Results. The FOG was reported by 8 (15%) patients with PD. The Apathy Scale score (p=0.018), Modified Hoehn and Yahr stage (p

The cerebellar reserve is defined as the capacity of the cerebellum for compensation and restoration following injury. This unique cerebellar ability is attributed to various forms of synaptic plasticity that incorporate multimodal and redundant cerebellar inputs, two major features of the cerebellar circuitry. It is assumed that the cerebellar reserve is acquired from the age of 12 years after the maturation of both the cerebellar adaptative behaviors and cerebellar functional connectivity. However, acquiring the cerebellar reserve is also affected by two other factors: vulnerability and growth potential in the developing cerebellum. First, cerebellar injury during the critical period of neural circuit formation (especially during fetal and neonatal life and infancy) leads to persistent dysfunction of the cerebellum and its targets, resulting in the limitation of the cerebellar reserve. Secondly, growth potential appears to facilitate cerebellar reserve during the stage when the cerebellar reserve is still immature. Based on these findings, the present mini-review proposes a possible developmental trajectory underlying the acquisition of cerebellar reserve. We highlight the importance of studies dedicated to the understanding of the cerebellar resilience to injuries.

Lesions in the Guillain–Mollaret (G–M) triangle frequently cause various types of tremors or tremor-like movements. Nevertheless, we know relatively little about their generation mechanisms. The deep cerebellar nuclei (DCN), which is a primary node of the triangle, has two main output paths: the primary excitatory path to the thalamus, the red nucleus (RN), and other brain stem nuclei, and the secondary inhibitory path to the inferior olive (IO). The inhibitory path contributes to the dentato-olivo-cerebellar loop (the short loop), while the excitatory path contributes to the cerebrocerebellar loop (the long loop). We propose a novel hypothesis: each loop contributes to physiologically distinct type of tremors or tremor-like movements. One type of irregular tremor-like movement is caused by a lesion in the cerebrocerebellar loop, which includes the primary path. A lesion in this loop affects the cerebellar forward model and deteriorates its accuracy of prediction and compensation of the feedback delay, resulting in irregular instability of voluntary motor control, i.e., cerebellar ataxia (CA). Therefore, this type of tremor, such as kinetic tremor, is usually associated with other symptoms of CA such as dysmetria. We call this type of tremor forward model-related tremor. The second type of regular tremor appears to be correlated with synchronized oscillation of IO neurons due, at least in animal models, to reduced degrees of freedom in IO activities. The regular burst activity of IO neurons is precisely transmitted along the cerebellocerebral path to the motor cortex before inducing rhythmical reciprocal activities of agonists and antagonists, i.e., tremor. We call this type of tremor IO-oscillation-related tremor. Although this type of regular tremor does not necessarily accompany ataxia, the aberrant IO activities (i.e., aberrant CS activities) may induce secondary maladaptation of cerebellar forward models through aberrant patterns of long-term depression (LTD) and/or long-term potentiation (LTP) of the cerebellar circuitry. Although our hypothesis does not cover all tremors or tremor-like movement disorders, our approach integrates the latest theories of cerebellar physiology and provides explanations how various lesions in or around the G–M triangle results in tremors or tremor-like movements. We propose that tremor results from errors in predictions carried out by the cerebellar circuitry.

The cerebellum is particularly enriched in antigens and represents a vulnerable target to immune attacks. Immune-mediated cerebellar ataxias (IMCAs) have diverse etiologies, such as gluten ataxia (GA), post-infectious cerebellitis (PIC), Miller Fisher syndrome (MFS), paraneoplastic cerebellar degeneration (PCD), opsoclonus myoclonus syndrome (OMS), and anti-GAD ataxia. Apart from these well-established entities, cerebellar ataxia (CA) occurs also in association with autoimmunity against ion channels and related proteins, synaptic adhesion/organizing proteins, transmitter receptors, glial cells, as well as the brainstem antigens. Most of these conditions manifest diverse neurological clinical features, with CAs being one of the main clinical phenotypes. The term primary autoimmune cerebellar ataxia (PACA) refers to ataxic conditions suspected to be autoimmune even in the absence of specific well-characterized pathogenic antibody markers. We review advances in the field of IMCAs and propose a clinical approach for the understanding and diagnosis of IMCAs, focusing on rare etiologies which are likely underdiagnosed. The frontiers of PACA are discussed. The identification of rare immune ataxias is of importance since they are potentially treatable and may lead to a severe clinical syndrome in absence of early therapy.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV2), the cause of the current pandemic coronavirus disease 2019 (COVID-19), primarily targets the respiratory system. Some patients also experience neurological signs and symptoms ranging from anosmia, ageusia, headache, nausea, and vomiting to confusion, encephalitis, and stroke. Approximately 36% of those with severe COVID-19 experience neurological complications. The virus may enter the central nervous system through the olfactory nerve in the nasal cavity and damage neurons in the brainstem nuclei involved in the regulation of respiration. Patients with cerebellar ataxia (CA) are particularly vulnerable to severe outcome if they contract COVID-19 because of the complexity of their disease, the presence of comorbidities, and their use of immunosuppressive therapies. Most CA patients burdened by progressive neurologic deficits have substantially impaired mobility and other essential functions, for which they rely heavily on ambulatory services, including rehabilitation and psychosocial care. Cessation of these interventions because of isolation restrictions places the CA patient population at risk of further deterioration. This international panel of ataxia experts provides recommendations for neurologists caring for patients with CA, emphasizing a pro-active approach designed to maintain their autonomy and well-being: continue long-term medications, promote rehabilitation efforts, utilize the technology of virtual visits for regular contact with healthcare providers, and pay attention to emotional and psychosocial health. Neurologists should play an active role in decision-making in those CA cases requiring escalation to intensive care and resuscitation. Multi-disciplinary collaboration between care teams is always important, and never more so than in the context of the current pandemic.

Current assessment of patients with cerebellar disorders is based on conventional neurological examination that is dependent on subjective judgements. Quantitative measurement of cerebellar ataxias (CAs) is essential for assessment of evidence-based treatments and the monitoring of the progress or recovery of diseases. It may provide us a useful tool to navigate future treatments for ataxia. We developed a Kinect v2. sensor system with a novel algorithm to measure and evaluate movements for two tests of Scale for the Assessment and Rating of Ataxia (SARA): the nose-finger test and gait. For the nose-finger test, we evaluated and compared accuracy, regularities and smoothness in the movements of the index finger and the proximal limbs between cerebellar patients and control subjects. For the task of walking, we evaluated and compared stability between the two groups. The precision of the system for evaluation of movements was smaller than 2 mm. For the nose-finger test, the mildly affected patients tended to show more instability than the control subjects. For a severely affected patient, our system quantified the instability of movements of the index finger using kinematic parameters, such as fluctuations and average speed. The average speed appears to be the most sensitive parameter that contrasts between patients with CAs and control subjects. Furthermore, our system also detected the adventitious movements of more proximal body parts, such as the elbow, shoulder and head. Assessment of walking was possible only in patients with mild CAs. They demonstrated large sways and compensatory wide stances. These parameters appeared to show higher accuracy than SARA. This examiner-independent device measures movements of the points of interest of SARA more accurately than eye and further provides additional information about the ataxic movements (e.g., the adventitious movements of the elbow, shoulder and head in the nose-finger test and the wide-based walking with large oscillation in the gait task), which is out of the scope of SARA. Our new system enables more accurate scoring of SARA and further provides additional information that is not currently evaluated with SARA. Therefore, it provides an easier, more accurate and more systematic description of CAs.

Long-term depression at parallel fibers-Purkinje cells (PF-PC LTD) is essential for cerebellar motor learning and motor control. Recent progress in ataxiology has identified dysregulation of PF-PC LTD in the pathophysiology of certain types of immune-mediated cerebellar ataxias (IMCAs). Auto-antibodies towards voltage-gated Ca channel (VGCC), metabotropic glutamate receptor type 1 (mGluR1), and glutamate receptor delta (GluR delta) induce dysfunction of PF-PC LTD, resulting in the development of cerebellar ataxias (CAs). These disorders show a good response to immunotherapies in non-paraneoplastic conditions but are sometimes followed by cell death in paraneoplastic conditions. On the other hand, in some types of spinocerebellar ataxia (SCA), dysfunction in PF-PC LTD, and impairments of PF-PC LTD-related adaptive behaviors (including vestibulo-ocular reflex (VOR) and prism adaptation) appear during the prodromal stage, well before the manifestations of obvious CAs and cerebellar atrophy. Based on these findings and taking into account the findings of animal studies, we re-assessed the clinical concept of LTDpathy. LTDpathy can be defined as a clinical spectrum comprising etiologies associated with a functional disturbance of PF-PC LTD with concomitant impairment of related adaptative behaviors, including VOR, blink reflex, and prism adaptation. In IMCAs or degenerative CAs characterized by persistent impairment of a wide range of molecular mechanisms, these disorders are initially functional and are followed subsequently by degenerative cell processes. In such cases, adaptive disorders associated with PF-PC LTD manifest clinically with subtle symptoms and can be prodromal. Our hypothesis underlines for the first time a potential role of LTD dysfunction in the pathogenesis of the prodromal symptoms of CAs. This hypothesis opens perspectives to block the course of CAs at a very early stage.

Cerebellar dysfunction can be associated with ataxia, dysarthria, dysmetria, nystagmus and cognitive deficits. While cerebellar dysfunction can be caused by vascular, traumatic, metabolic, genetic, inflammatory, infectious, and neoplastic events, the cerebellum is also a frequent target of autoimmune attacks. The underlying cause for this vulnerability is unclear, but it may be a result of region-specific differences in blood–brain barrier permeability, the high concentration of neurons in the cerebellum and the presence of autoantigens on Purkinje cells. An autoimmune response targeting the cerebellum—or any structure in the CNS—is typically accompanied by an influx of peripheral immune cells to the brain. Under healthy conditions, the brain is protected from the periphery by the blood–brain barrier, blood–CSF barrier, and blood–leptomeningeal barrier. Entry of immune cells to the brain for immune surveillance occurs only at the blood-CSF barrier and is strictly controlled. A breakdown in the barrier permeability allows peripheral immune cells uncontrolled access to the CNS. Often—particularly in infectious diseases—the autoimmune response develops because of molecular mimicry between the trigger and a host protein. In this review, we discuss the immune surveillance of the CNS in health and disease and also discuss specific examples of autoimmunity affecting the cerebellum.

Goal-directed movements are predictive and multimodal in nature, especially for moving targets. For instance, during a reaching movement for a moving target, humans need to predict both motion of the target and movement of the limb. Recent computational studies show that the cerebellum predicts current and future states of the body and its environment using internal forward models. Sensory feedback signals from the periphery have delays in reaching the central nervous system, ranging between tens to hundreds of milliseconds. It is well known in engineering that feedback control based on time-delayed inputs can result in oscillatory and often unstable movements. In contrast, the brain predicts a current state from a previous state using forward models. This predictive mechanism most likely underpins stable and dexterous control of reaching movements. Although the cerebro-cerebellum has long been suggested as loci of various forward models, few methods are available to evaluate accuracy of the forward models in patients with cerebellar ataxia. Recently, we developed a non-invasive method to analyze receipt of motor commands in terms of movement kinematics for the wrist joint (Br/Kr ratio). In the present study, we have identified two components (F1 and F2) of the smooth pursuit movement. We found that the two components were in different control modes with different Br/Kr ratios. The major F1 component in a lower frequency range encodes both velocity and position of the moving target (higher Br/Kr ratio) to synchronize movement of the wrist joint with motion of the target in a predictive manner. The minor F2 component in a higher frequency range is biased to position control in order to generate intermittent small step-wise movements. In cerebellar patients, the F1 component shows a selective decrease in the Br/Kr ratio, which is correlated with decrease in accuracy of the pursuit movement. We conclude that the Br/Kr ratio of the F1 component provides a unique parameter to evaluate accuracy of the predictive control. We also discuss the pathophysiological and clinical implications for clinical ataxiology.

The cerebellum is endowed with the capacity for compensation and restoration after pathological injury, a property known as cerebellar reserve. Such capacity is attributed to two unique morphological and physiological features of the cerebellum. First, mossy fibers that convey peripheral and central information run mediolaterally over a wide area of the cerebellum, resulting in the innervation of multiple microzones, commonly known as cerebellar functional units. Thus, a single microzone receives redundant information that can be used in pathological conditions. Secondly, the circuitry is characterized by a co-operative interplay among various forms of synaptic plasticity. Recent progress in understanding the mechanisms of redundant information and synaptic plasticity has allowed outlining therapeutic strategies potentiating these neural substrates to enhance the cerebellar reserve, taking advantage of the unique physiological properties of the cerebellum which appears as a modular and potentially reconfiguring brain structure.

The terminology of cerebellar dysmetria embraces a ubiquitous symptom in motor deficits, oculomotor symptoms, and cognitive/emotional symptoms occurring in cerebellar ataxias. Patients with episodic ataxia exhibit recurrent episodes of ataxia, including motor dysmetria. Despite the consensus that cerebellar dysmetria is a cardinal symptom, there is still no agreement on its pathophysiological mechanisms to date since its first clinical description by Babinski. We argue that impairment in the predictive computation for voluntary movements explains a range of characteristics accompanied by dysmetria. Within this framework, the cerebellum acquires and maintains an internal forward model, which predicts current and future states of the body by integrating an estimate of the previous state and a given efference copy of motor commands. Two of our recent studies experimentally support the internal-forward-model hypothesis of the cerebellar circuitry. First, the cerebellar outputs (firing rates of dentate nucleus cells) contain predictive information for the future cerebellar inputs (firing rates of mossy fibers). Second, a component of movement kinematics is predictive for target motions in control subjects. In cerebellar patients, the predictive component lags behind a target motion and is compensated with a feedback component. Furthermore, a clinical analysis has examined kinematic and electromyography (EMG) features using a task of elbow flexion goal-directed movements, which mimics the finger-to-nose test. Consistent with the hypothesis of the internal forward model, the predictive activations in the triceps muscles are impaired, and the impaired predictive activations result in hypermetria (overshoot). Dysmetria stems from deficits in the predictive computation of the internal forward model in the cerebellum. Errors in this fundamental mechanism result in undershoot (hypometria) and overshoot during voluntary motor actions. The predictive computation of the forward model affords error-based motor learning, coordination of multiple degrees of freedom, and adequate timing of muscle activities. Both the timing and synergy theory fit with the internal forward model, microzones being the elemental computational unit, and the anatomical organization of converging inputs to the Purkinje neurons providing them the unique property of a perceptron in the brain. We propose that motor dysmetria observed in attacks of ataxia occurs as a result of impaired predictive computation of the internal forward model in the cerebellum.

In the last years, different kinds of limbic encephalitis associated with autoantibodies against ion channels and synaptic receptors have been described. Many studies have demonstrated that such autoantibodies induce channel or receptor dysfunction. The same mechanism is discussed in immune-mediated cerebellar ataxias (IMCAs), but the pathogenesis has been less investigated. The aim of the present review is to evaluate what kind of cerebellar ion channels, their related proteins, and the synaptic machinery proteins that are preferably impaired by autoantibodies so as to develop cerebellar ataxias (CAs). The cerebellum predictively coordinates motor and cognitive functions through a continuous update of an internal model. These controls are relayed by cerebellum-specific functions such as precise neuronal discharges with potassium channels, synaptic plasticity through calcium signaling pathways coupled with voltage-gated calcium channels (VGCC) and metabotropic glutamate receptors 1 (mGluR1), a synaptic organization with glutamate receptor delta (GluRδ), and output signal formation through chained GABAergic neurons. Consistently, the association of CAs with anti-potassium channel-related proteins, anti-VGCC, anti-mGluR1, and GluRδ, and anti-glutamate decarboxylase 65 antibodies is observed in IMCAs. Despite ample distributions of AMPA and GABA receptors, however, CAs are rare in conditions with autoantibodies against these receptors. Notably, when the autoantibodies impair synaptic transmission, the autoimmune targets are commonly classified into three categories: release machinery proteins, synaptic adhesion molecules, and receptors. This physiopathological categorization impacts on both our understanding of the pathophysiology and clinical prognosis.

Various etiopathologies affect the cerebellum, resulting in the development of cerebellar ataxias (CAs), a heterogeneous group of disorders characterized clinically by movement incoordination, affective dysregulation, and cognitive dysmetria. Recent progress in clinical and basic research has opened the door of the ‘‘era of therapy” of CAs. The therapeutic rationale of cerebellar diseases takes into account the capacity of the cerebellum to compensate for pathology and restoration, which is collectively termed cerebellar reserve. In general, treatments of CAs are classified into two categories: cause-cure treatments, aimed at arresting disease progression, and neuromodulation therapies, aimed at potentiating cerebellar reserve. Both forms of therapies should be introduced as soon as possible, at a time where cerebellar reserve is still preserved. Clinical studies have established evidence-based cause-cure treatments for metabolic and immune-mediated CAs. Elaborate protocols of rehabilitation and non-invasive cerebellar stimulation facilitate cerebellar reserve, leading to recovery in the case of controllable pathologies (metabolic and immune-mediated CAs) and delay of disease progression in the case of uncontrollable pathologies (degenerative CAs). Furthermore, recent advances in molecular biology have encouraged the development of new forms of therapies: the molecular targeting therapy, which manipulates impaired RNA or proteins, and the neurotransplantation therapy, which delays cell degeneration and facilitates compensatory functions. The present review focuses on the therapeutic rationales of these recently developed therapeutic modalities, highlighting the underlying pathogenesis.

ObjectiveThe aim of this study was to assess quantitatively the gait disorders in the daily lives of patients with Parkinson’s disease (PD) using with a newly developed portable gait rhythmogram (PGR), which has a trunk-mounted acceleration sensor and automatic gait-detection algorithm.MethodsUsing the PGR, we recorded the daily walking profiles of 14 PD patients before and after the addition or increase in dose of an MAO-B inhibitor (selegiline, average dose: 4.0 mg/day) as part of their medicine regimen, and evaluated their gait using the unified Parkinson’s disease rating scale (UPDRS) and scores from a freezing of gait (FOG) questionnaire.ResultsBefore treatment with selegiline, the overall movements per 24 h was decreased below 0.41 m/s2 (mean − 1.5 SD) in eight patients. The mean gait acceleration was decreased below 1.94 m/s2 (mean − 2 SD) in 10 patients. The slope of the linear regression line was increased to 1.6 (mean + 1.5 SD) in eight patients. The cadence was increased to 124 steps/min (mean + 1.5 SD) in four patients. Based on continuous PGR recordings in the daily lives of the patients for 24 h, the addition or increase in dose of selegiline increased the amplitudes of gait accelerations in 4 of 10 patients (40.0%), widened the range of gait accelerations in 5 of 8 patients (62.5%), diminished the cadence in 4 of 4 patients (100%), and diminished the fluctuations in gait throughout the day in 12 of 14 patients (85.7%). The UPDRS III and FOG scores significantly improved after the addition or increase in dose of selegiline (p

Long-term and objective monitoring is necessary for full assessment of the condition of patients with Parkinson’s disease (PD). Recent advances in biotechnology have seen the development of various types of wearable (body-worn) sensor systems. By using accelerometers and gyroscopes, these devices can quantify motor abnormalities, including decreased activity and gait disturbances, as well as nonmotor signs, such as sleep disturbances and autonomic dysfunctions in PD. This review discusses methodological problems inherent in wearable devices. Until now, analysis of the mean values of motion-induced signals on a particular day has been widely applied in the clinical management of PD patients. On the other hand, the reliability of these devices to detect various events, such as freezing of gait and dyskinesia, has been less than satisfactory. Quantification of disease-specific changes rather than nonspecific changes is necessary.

Reports suggesting a pathogenic role of autoantibodies directed against glutamic acid decarboxylase 65 (GAD65Abs) in cerebellar ataxias (CAs) are reviewed, and debatable issues such as internalization of antibodies by neurons and roles of epitopes are discussed. GAD65 is one of two enzymes that catalyze the conversion of glutamate to the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). A pathogenic role of GAD65Ab in CAs is suggested by in vivo and in vitro studies. (1) Intracerebellar administration of cerebrospinal fluid (CSF) immunoglobulins (IgGs) obtained from GAD65Ab-positive CA patients impairs cerebellar modulation of motor control in rats. (2) CSF IgGs act on terminals of GABAergic neurons and decrease the release of GABA in cerebellar slices from rats and mice. (3) Absorption of GAD65Ab by recombinant GAD65 diminishes the above effects, and monoclonal human GAD65Ab (b78) mimic the effects of CSF IgGs in vivo and in vitro. Studies using GAD65-KO mice confirm that the target molecule is GAD65. (4) Notably, the effects of GAD65Ab depend on the epitope specificity of the monoclonal GAD65Ab. Taken together, these results indicate that epitope-specific GAD65Ab-induced impairment of GABA release is involved in the pathogenesis of GAD65Ab-positive CA and support the early detection of GAD65Ab-associated CA to initiate immunotherapy before irreversible neuronal death in the cerebellum.

Cerebellar ataxias represent a group of heterogeneous disorders impacting on activities of daily living and quality of life. Various therapies have been proposed to improve symptoms in cerebellar ataxias. This review examines the physiological background of the various treatments currently administered worldwide. We analyze the mechanisms of action of drugs with a focus on aminopyridines and other antiataxic medications, of noninvasive cerebellar stimulation, and of motor rehabilitation. Considering the cerebellum as a controller, we propose the novel concept of ‘restorable stage’. Because of its unique anatomical architecture and its diffuse connectivity in particular with the cerebral cortex, keeping in mind the anatomophysiology of the cerebellar circuitry is a necessary step to understand the rationale of therapies of cerebellar ataxias and develop novel therapeutic tools.

The aim of this study was to analyze the association between the amount of daily movement measured with a triaxial accelerometer (MIMAMORI-Gait) and motor symptoms in patients with Parkinson’s disease (PD). The subjects were 50 consecutive patients with untreated PD free of dementia. The amount of overall movement over 24 h was measured with the portable MIMAMORI-Gait device and its association with the modified Hoehn and Yahr stage and UPDRS part II and III scores was analyzed. In patients with PD, the amount of overall movement measured with MIMAMORI-Gait was significantly associated with the UPDRS part II score (β = −0.506, p < 0.001) and part III score (β = −0.347, p = 0.010), but not with the modified Hoehn and Yahr stage. The amount of overall movement measured with MIMAMORI-Gait can potentially be used for evaluation of motor symptoms and ADL in PD patients.

The clinical category of immune-mediated cerebellar ataxias (IMCAs) is now recognized after 3 decades of clinical and experimental research. The cerebellum gathers about 60% of neurons in the brain, is enriched in numerous plasticity mechanisms, and presents a large variety of antigens at the neuroglial level: ion channels and related proteins, synaptic adhesion/organizing proteins, transmitter receptors, and glial cells. Cerebellar circuitry is especially vulnerable to immune attacks. After the loss of immune tolerance, IMCAs present in an acute or subacute manner with various combinations of a vestibulocerebellar syndrome (VCS), a cerebellar motor syndrome (CMS), and a cerebellar cognitive affective syndrome/Schmahmann's syndrome (CCAS/SS). IMCAs include gluten ataxia (GA), post-infectious cerebellitis (PIC), Miller Fisher syndrome (MFS), paraneoplastic cerebellar degeneration (PCD), opsoclonus myoclonus syndrome (OMS), anti-glutamic acid decarboxylase (anti-GAD) ataxia, and glial fibrillary acidic protein (GFAP) astrocytopathy (GFAPA). In addition, multiple sclerosis (MS), acute disseminated encephalomyelitis (ADEM), Behçet disease, and collagen-vascular disorders may also present with cerebellar symptoms when lesions involve cerebellar afferences/efferences. Patients whose clinical profiles do not fit with IMCAs are now gathered in the group of primary autoimmune cerebellar ataxias (PACAs). Latent auto-immune cerebellar ataxia (LACA) refers to a clinical stage with a slow progressive course and a lack of obvious auto-immune background. At a pre-symptomatic stage, patients remain asymptomatic, whereas at the prodromal stage aspecific symptoms occur, announcing the symptomatic neuronal loss. LACA corresponds to a time-window where an intervention could lead to preservation of plasticity mechanisms. Patients may evolve from LACA to PACA and typical IMCAs, highlighting a continuum. Immune ataxias represent a model to elucidate the sequence of events leading to destruction of cerebellar neuronal reserve and develop novel strategies aiming to restore plasticity mechanisms. [ABSTRACT FROM AUTHOR]