Cerebellum最新文献

Essential Tremor (ET) is the most common movement disorder and has a worldwide prevalence of 1%, including 5% of the population over 65 years old. It is characterized by an active, postural or kinetic tremor, primarily affecting the upper limbs, and is diagnosed based on clinical characteristics. The pathological mechanisms of ET, however, are mostly unknown. Moreover, despite its high heritability, genetic studies of ET genetics have yielded mixed results. Transcriptomics is a field that has the potential to reveal valuable insights about the processes and pathogenesis of ET thus providing an avenue for the development of more effective therapies. With the emergence of techniques such as single-cell and single-nucleus RNA sequencing (scRNA-seq and snRNA-seq), molecular and cellular events can now be more closely examined, providing valuable insights into potential causal mechanisms. In this review, we review the growing literature on transcriptomic studies in ET, aiming to identify biological pathways involved and explore possible avenues for further ET research. We emphasized the convergence on shared of biological pathways across several studies, specifically axonal guidance and calcium signaling. These findings posit multiple hypotheses linking both pathways through the regulation of axonal and synaptic plasticity. We conclude that increasing the sample size is vital to uncover the subtleties of ET clinical and pathological heterogeneity. Additionally, integrating Multiomics approaches should provide a comprehensive understanding of the disease's pathophysiology.

Alexander's law states that spontaneous nystagmus increases when looking in the direction of fast-phase and decreases during gaze in slow-phase direction. Disobedience to Alexander's law is occasionally observed in central nystagmus, but the underlying neural circuit mechanisms are poorly understood. In a retrospective analysis of 2,652 patients with posterior circulations stroke, we found a violation of Alexander's law in one or both directions of lateral gaze in 17 patients with lesions of unilateral lateral medulla affecting the vestibular nucleus. Patients with vestibular neuritis served as a control. When Alexander's law is violated, the time constant (Tc) was larger than that in the controls (median [interquartile range, IQR]: 14.4s [6.4-38.9] vs 9.0s [IQR 5.5-12.6], p = 0.036) while the Tc did not differ between the groups when Alexander' law is obeyed (9.6s [3.6-16.1] vs 9.0s [5.5-12.6], p = 0.924). To test the study hypothesis that an unstable neural integrator may generate nystagmus violating Alexander's law, we utilized the gaze-holding neural integrator model incorporating brainstem leaky neural integrator and negative velocity feedback loop via the cerebellum. The lesion-induced changes included false rotational cue, primarily attributed to central vestibular imbalance, and unstable neural integrator, examined in two ways: hyperexcitable brainstem neural integrator and paradoxical excitatory effect of Purkinje cells. With normal integrator function, the false rotational cue generated nystagmus consistent with Alexander's law. However, both types of unstable neural integrators tested produced nystagmus that violated Alexander's law. We propose that when the neural integrator is unstable with lesions in the brainstem neural integrator itself or the neural synapse between Purkinje cells and the brainstem vestibular nucleus, nystagmus violates Alexander's law. The spontaneous nystagmus violating Alexander's law may be the useful clue for identifying central vestibular syndrome.

While the cerebellum's role in orchestrating motor execution and routines is well established, its functional role in supporting cognition is less clear. Previous studies claim that motricity and cognition are mapped in different areas of the cerebellar cortex, with an anterior/posterior dichotomy. However, most of the studies supporting this claim either use correlational methods (neuroimaging) or are lesion studies that did not consider central covariates (such as age, gender, treatment presence, and deep nuclei impairment) known to influence motor and cognitive recoveries in patients. Here, we used voxel-based lesion-symptom mapping (VLSM) on children and young adults having undergone cerebellar tumor resection. This approach allows to control for these covariates and evaluate causal relationships between brain anatomy and behavioral performances to disentangle the anatomic substrate of motor and cognitive functions. VLSM analyses showed that both motor and cognitive impairments were greater in children and young adults with lesions of the posterior cerebellum. These results highlight distinct and overlapping structural correlates of motor and cognitive performance in the cerebellum and are consistent with structural and functional hypotheses of integration of the cerebellum in motor and cognitive functions.

Historically, Friedreich's Ataxia (FRDA) has been linked to a relatively preserved cerebellar cortex. Recent advances in neuroimaging have revealed altered cerebello-cerebral functional connectivity (FC), but the extent of intra-cerebellar FC changes and their impact on cognition remains unclear. This study investigates intra-cerebellar FC alterations and their cognitive implications in FRDA. In this cross-sectional, single-center study, resting-state functional MRI data from 17 patients with FRDA (average age 27.7 ± 13.6 years; F/M = 6/11) and 20 healthy controls (HC) (average age 29.4 ± 9.7 years; F/M = 9/11), all of whom underwent neuropsychological testing, were analyzed. From functional connectivity matrices, graph measures were computed at both the network and node levels using two complementary parcellations. FRDA patients exhibited decreased global efficiency (p = 0.04), nodal degree (p = 0.001) and betweenness centrality (p = 0.04) in the vermal portion of lobule VIII, along with reduced global efficiency in cerebellar regions belonging to the Control-A network (p = 0.02), one of the three subdivisions of the Frontoparietal network. Verbal memory deficits correlated with global efficiency in both the vermal portion of lobule VIII (r = 0.53, p = 0.02) and the cerebellar regions of the Control-A network (r = 0.49, p = 0.05). Graph analysis revealed regional intra-cerebellar FC changes in FRDA, marked by reduced functional centrality in cerebellar regions of the vermis and responsible for executive functions. These changes correlated with cognitive alterations, highlighting the role of the cerebellar cortex in the cognitive impairment observed in FRDA.

The cerebellum is involved in non-motor processing, supported by topographically distinct cerebellar activations and closed-loop circuits between the cerebellum and the cortex. Disruptions to cerebellar function may negatively impact prefrontal function and processing. Cerebellar resources may be important for offloading cortical processing, providing crucial scaffolding for normative performance and function. Here, we used transcranial direct current stimulation (tDCS) to temporarily alter cerebellar function and subsequently investigated resting state network connectivity. Critically, what happens to these circuits if the cerebellum is not functioning optimally, or after stimulation, remains relatively unknown. We employed a between-subjects design with 74 participants total (38 female; M = 22.0 years, SD = 3.45), applying anodal (n = 25), cathodal (n = 25), or sham (n = 24) stimulation to the cerebellum to examine the effect of stimulation on cerebello-cortical resting state connectivity in young adults. We predicted increased functional connectivity following cathodal stimulation and decreased functional connectivity following anodal stimulation. We found, anodal stimulation resulted in increased connectivity in both ipsilateral and contralateral regions of the cortex, perhaps indicative of a compensatory response to degraded cerebellar output. Additionally, a window analysis also demonstrated a time dependent nature to the impacts of cerebellar tDCS on connectivity, particularly with cognitive regions of the cerebral cortex. This work suggests that when cerebellar outputs are degraded, in this case by tDCS, the cerebellum offloads its processing responsibility which encourages more cortical regions to engage to compensate for the degraded cerebellar output. This results in in differences in cortical activation patterns and performance deficits. These results might inform and update existing compensatory models, which focus primarily on the cortex, to include the cerebellum as a vital structure involved in the scaffolding of cortical processing.

Cerebellar functional and structural connectivity are likely related to motor function after stroke. Less is known about motor recovery, which is defined as a gain of function between two time points, and about the involvement of the cerebellum. Fifteen patients who were hospitalized between 2018 and 2020 for a first cerebral ischemic event with persistent upper limb deficits were assessed by resting-state functional MRI (rsfMRI) and clinical motor score measurements at 3, 9 and 15 weeks after stroke. Age- and sex-matched healthy subjects (n = 15) were assessed once. The objectives were (1) to study whether the level of connectivity between the contralesional cerebellum (lobules IV-V-VI and lobule VIII) and the ipsilesional motor regions on rsfMRI is predictive of motor recovery and (2) to compare these connectivities with those of healthy subjects. Upper limb motor recovery was positively correlated with functional connectivity between contralesional cerebellar lobule VIII and the ipsilesional supplementary motor area (SMA). The greater the connectivity between these regions, the better the motor recovery. In patients, the corticocerebellar network between lobule IV-V-VI and the ipsilesional M1 and SMA showed weaker synchronization at rest than in healthy subjects. Cortico-cortical connectivity was not associated with recovery. Resting-state functional connectivity, including contralesional cerebellar lobule VIII, could be a tool for studying and predicting recovery in stroke patients. Our study highlights the role of the cerebellum in motor recovery after stroke, enabling us to consider new therapeutic targets in neuromodulation.

While deficits in episodic memory have been noted following cerebellar damage, there is a lack of research systematically exploring the socio-demographic and cognitive profiles of patients with such impairments. This study aimed to differentiate between chronic-phase cerebellar stroke patients with and without verbal episodic memory deficits, and to determine whether those with deficits exhibit distinct socio-demographic and clinical profiles, thereby identifying potential factors associated with these impairments. Data from 15 cerebellar stroke patients in the CEREBEMO cohort were analyzed, with participants categorized into two groups based on verbal episodic memory performance: deficits (n = 8) and no deficits (n = 7). Statistical analyses, including Generalized Linear Mixed Models and Chi-Squared tests, compared socio-demographic and neuropsychological variables between the groups. Significant differences were observed in socio-educational levels, with a higher proportion of patients with memory deficits at intermediate education levels. Moreover, patients with memory deficits performed worse on the Montreal Cognitive Assessment and the Trail Making Test, indicating overall lower cognitive efficiency and slower processing speed. Post-hoc analysis showed that, despite the limited sample size, our sample effectively detected a significant difference between the two groups with high statistical power. These findings highlight potential socio-educational and cognitive factors associated with memory impairments following cerebellar stroke.

Pediatric cerebellar tumor survivors may present with spontaneous language impairments following treatment, but the nature of these impairments is still largely unclear. A recent study by Svaldi et al. (Cerebellum. 23:523-44, 2023) found a broad spectrum of spontaneous language impairments irrespective of postoperative cerebellar mutism syndrome (pCMS) diagnosis in long-term pediatric cerebellar tumor survivors. Several patients presented with reduced grammatical or lexical accuracy, but a detailed error analysis was lacking. The present study builds on this study by 1) investigating the error types in spontaneous language across three language processing levels in the same participant group and 2) by evaluating the possible association between pCMS and the processing nature of the language impairments. Spontaneous language was evaluated in 12 long-term survivors of pediatric cerebellar tumors (M(SD) = 4;8(3;8) years), of whom five were diagnosed with pCMS. The proportion of occurrence of each error type was compared between each patient and five matched controls using individual case statistics, reflecting (lexico-)phonological (i.e., phonemic paraphasias), lexical-semantic (e.g., empty speech) and morphosyntactic processing (e.g., verb inflection errors). Each patient showed a significantly higher proportion of at least one of the included error types across all language processing levels. A higher proportion of general-all-purpose verbs and inaccurate verb inflection were the most common errors and respectively reflected lexical-semantic and morphosyntactic processing. Additional language impairments were identified using the error analysis that were not identified with standard language measures and psycholinguistic analysis, suggesting the added diagnostic value of error analyses.

A 50-year-old woman with a 20-year history of gait instability presented with new-onset vertigo and oscillopsia. Examination revealed bilateral vestibular loss, cerebellar ataxia, sensory neuropathy, a "yes-yes" head tremor, nystagmus and a family history of a similar syndrome. Genetic testing for cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (RFC1) was negative, but whole exome sequencing identified a novel mutation in the DNA methyltransferase 1 (DNMT1) gene, broadening the differential diagnosis for this phenotype. Management was focused on symptomatic treatment and genetic counseling. This case highlights the importance of considering DNMT1 mutations in patients with a similar clinical presentation.

Autosomal-recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is an early-onset neurodegenerative disease caused by mutations in the SACS gene. The first two mutations were identified in French Canadian populations 20 years ago. The disease is now known as one of the most frequent recessive ataxias worldwide. Prominent features include cerebellar ataxia, pyramidal spasticity, and neuropathy. Neuropathological findings revealed cerebellar atrophy of the superior cerebellar vermis and the anterior vermis associated with Purkinje cell death, pyramidal degeneration, cortical atrophy, loss of motor neurons, and demyelinating neuropathy. No effective therapy is available for ARSACS patients but, in the last two decades, there have been significant advances in our understanding of the disease. New approaches in ARSACS, such as the reprogramming of induced pluripotent stem cells derived from patients, open exciting perspectives of discoveries. Several research questions are now emerging. Here, we review the clinical features of ARSACS as well as the cerebellar aspects of the disease, with an emphasis on recent fields of investigation.