Cerebellum最新文献

Otolith-ocular reflex (OOR) (contralateral ocular torsion [ocular counter-roll, OCR] and skew deviation [upward deviation of the lowermost eye and/or downward deviation of the uppermost eye]), helps to maintain eye position and stabilize fixation in response to head and/or body tilt in the roll plane. While prominent in lateral-eyed animals, OOR is vestigial in humans, indicating the frontal-eyed system has evolved to inhibit this reflex. We show that OOR can be released under pathological conditions. We describe a patient with anti-Ma2-associated rhombencephalitis manifesting with hyperactive OOR, suggesting cerebellar inhibition failure over OOR brainstem machinery. A 38-year-old male presented with a 6-month history of vertical binocular diplopia exclusively elicited during head tilt to the sides, and difficulty looking down. During head tilts, there was marked OCR in both eyes and prominent hyperdeviation of the lowermost eye. There was additional supranuclear vertical saccadic palsy. Brain MRI showed mild midbrain atrophy. There were high titers of anti-Ma2 antibodies both in serum and CSF, linked to the presence of a mediastinal seminoma. Treatment with anti-inflammatory drugs was ineffective, and tumor-directed therapy was further planned. Hyperactive otolith-ocular reflex (rabbit's eye sign) is a unique finding in humans. Its presence warrants the investigation of cerebellar/brainstem disease.

Perineuronal nets (PNNs) are condensed extracellular matrix structures that regulate synaptic plasticity and neuronal stability. While their distribution and function have been well characterized in rodents, PNNs remain largely understudied in the human cerebellum. Here, we provide an anatomical characterization of PNNs in the post-mortem human cerebellum and compare their distribution and cellular phenotypes with those in mouse and macaque cerebellum. Using immunofluorescence for both Wisteria floribunda lectin (WFL) and aggrecan, we observed that PNNs in humans were exclusively localized in the deep cerebellar nuclei (DCN), with no detectable labelling in cerebellar cortex. In contrast, both macaques and mice exhibited PNNs in the DCN and cortex (granule cell layer), with interspecies differences in density and marker co-localization. Combining immunolabeling with fluorescence in situ hybridization for SLC17A7, GAD1, and PVALB, we found that in human and mouse DCN, PNNs predominantly surrounded excitatory, parvalbumin-expressing neurons, whereas in macaques, PV expression was absent from PNN-enwrapped excitatory cells. These findings highlight both conserved and divergent features of cerebellar PNNs, providing novel insights into the potential functional roles of these structures in human cerebellar circuitry, with implications for understanding cerebellar plasticity and disease vulnerability.

Cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS) and spinocerebellar ataxia type 27B (SCA27B) are two increasingly recognized types of late-onset ataxia caused by biallelic RFC1 AAGGG and heterozygous FGF14 GAA repeat expansions, respectively. We describe three siblings of Greek-Cypriot origin with late-onset cerebellar ataxia. Two brothers carried biallelic pathogenic RFC1 AAGGG expansions and heterozygous FGF14 GAA expansions (338-350 repeats), establishing a dual diagnosis of CANVAS and SCA27B. Both presented with progressive gait ataxia, vestibular dysfunction, and sensory neuronopathy; one also reported episodic symptoms typical of SCA27B. Their sister, heterozygous for RFC1 and carrying a pathogenic FGF14 expansion (325 repeats), showed a pure SCA27B phenotype with episodic fluctuations, but without neuropathy or vestibular involvement. Brain MRI in all three demonstrated mild-to-moderate vermian atrophy. To our knowledge, this is the first documented report of co-occurring CANVAS and SCA27B in the same individuals. The findings expand the phenotypic spectrum of late-onset ataxia and highlight the importance of continued genetic testing, even after an initial diagnosis has been made.

Growing experimental and clinical evidence demonstrates that immune activation influences Spinocerebellar Ataxia type 2 (SCA2) phenotype, yet the specific role of proinflammatory cytokines remains unexplored. This stuyd aims to measure peripheral proinflammatory cytokine concentrations in SCA2 patients and examine their associations with clinical, genetic, and inflammatory markers. We measured serum levels of interleukin-1α (IL-1α), interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor-α (TNF-α) using enzyme-linked immunosorbent assay in 36 spinocerebellar ataxia type 2 patients and 36 matched controls. Clinical evaluation encompassed the Scale for Assessment and Rating of Ataxia (SARA), Inventory of Non-Ataxia Symptoms count (INAS), Cerebellar Cognitive Affective Syndrome scale (CCAS-S), along with S100β protein levels and cellular inflammatory markers. We employed univariate correlation analyses to examine relationships between cytokine levels and disease characteristics. SCA2 patients demonstrated cytokine profiles similar to healthy controls, with the exception of significantly elevated IL-8 levels. Spearman correlation analysis revealed that the monocyte-to-lymphocyte ratio (MLR) was directly associated with IL-8 concentrations. Notably, no significant associations were found between the cytokine levels and demographic characteristics, age at onset, time from ataxia onset, CAG repeat length, or clinical markers of disease severity. Our study reveals selective peripheral IL-8 elevation in SCA2, independent of disease severity. While not linked to disease severity, this immune signature warrants further research to assess its prognostic or therapeutic value through larger, longitudinal studies.

Genetic variation in CACNA1D, the gene that encodes the pore-forming subunit of the L-type calcium channel Ca_V1.3, has been associated with increased risk for neuropsychiatric disorders that display abnormalities in cerebellar structures. We sought to clarify if deletion of Ca_V1.3 in mice would induce abnormalities in cerebellar cortex cytoarchitecture or synapse morphology. Since Ca_V1.3 is highly expressed in cerebellar molecular layer interneurons (MLIs) and L-type channels appear to regulate GABA release from MLIs, we hypothesized that loss of Ca_V1.3 would alter GABAergic synapses between MLIs and Purkinje cells (PCs) without altering MLI density or PC structure. As expected, we did not observe changes in the density of MLIs or PCs. Surprisingly, Ca_V1.3 KO mice do have decreased complexity of PC dendritic arbors without differences in the number or structure of GABAergic synapses onto PCs. Loss of Ca_V1.3 was not associated with impaired acquisition of delay eyeblink conditioning. Therefore, our data suggest that Ca_V1.3 expression is important for PC structure but does not affect other measures of cerebellar cortex morphology or cerebellar function as assessed by delay eyeblink conditioning.

Spinocerebellar ataxia type 2 (SCA2) is a neurodegenerative disorder characterized by cerebellar motor symptoms. The extent and timing of cognitive involvement, particularly in pre-ataxic carriers, remain unclear. To assess cognitive performance across clinical stages of SCA2 and investigate early neurocognitive changes in pre-ataxic individuals. We evaluated 52 genetically confirmed participants from a rural Brazilian cohort: 16 pre-ataxic carriers, 12 symptomatic patients, and 24 intrafamilial controls. A standardized neuropsychological battery assessed global cognition, executive function, memory, visuospatial abilities, attention/working memory, mood, and language. Group comparisons and correlations were adjusted using False Discovery Rate (FDR) correction. Pre-ataxic carriers performed comparably to their intrafamilial controls across all cognitive domains, with no significant group differences except for the FAB total score, and showed no associations with estimated time to disease onset. Executive dysfunction emerged as the most prominent cognitive feature of manifest SCA2 and was more strongly associated with CAG repeat length than with clinical disease markers. In this genetically and environmentally homogeneous cohort, only limited measurable cognitive impairment was observed in pre-ataxic carriers. These findings underscore the importance of longitudinal and multimodal studies to elucidate the timing and underlying mechanisms of cognitive decline in SCA2.

This study investigated the effects of repetitive transcranial magnetic stimulation (rTMS) over the right cerebellar hemisphere on visuomotor adaptation and interlimb coordination learning. Specifically, we examined the impact of cerebellar stimulation on the acquisition of new visuomotor transformations and subsequent adaptation under interference conditions during a bimanual tracking task. A total of 42 healthy adults performed a bimanual visuomotor tracking task in which the left and right hands controlled horizontal and vertical cursor movements, respectively. The experiment consisted of two phases: (1) an Initial learning phase involving adaptation to a visuomotor transformation, and (2) an Interference adaptation phase, defined as adaptation to a new visuomotor mapping under interference from the previously learned transformation, in which only the right-hand mapping was altered. Participants received either active or sham 1Hz rTMS over the right cerebellar hemisphere before the task. Performance was assessed using tracking error and interlimb error structure measures. Tracking errors decreased over trials in both learning phases. While rTMS had no significant effect during the Initial learning phase, it significantly reduced tracking errors during the Interference adaptation phase. In the active-rTMS group, interlimb error correlation and the directional error slope also declined across trials, suggesting reduced cross-limb interference and enhanced coordination flexibility. These findings suggest that cerebellar rTMS facilitates the adaptation of altered visuomotor mappings, particularly during interference adaptation, by modulating interlimb coordination. The results support the hypothesis that bimanual coordination relies on modular internal models that dynamically interact during motor learning. This study underscores the cerebellum's essential role in optimizing interlimb adaptation, especially under interference adaptation, and highlights the potential of cerebellar neuromodulation for motor rehabilitation.

The cerebellum undergoes significant age-related changes linked to poor balance in older adults. Although multi-session cerebellar iTBS combined with rehabilitation has been used in some clinical populations, its isolated effects in community-dwelling healthy older adults remain unknown, particularly in context of balance control and underlying cerebellar-motor cortex (M1) interactions. We tested whether a single-session, sham-controlled, cerebellar iTBS-only intervention could modulate balance and cerebellar-motor cortex (M1) interactions in community-dwelling older adults without neurological disease. The effects of cerebellar intermittent theta-burst stimulation (iTBS) on balance control and underlying cerebellar-motor cortex (M1) interactions in this population remain unclear. We investigated whether cerebellar iTBS led to [1] improved standing balance, and [2] changes in cerebellar-M1interactions measured using cerebellar brain inhibition (CBI) in older adults. Forty older adults were randomized to receive Active (n = 20) or Sham (n = 20) iTBS to the right lateral cerebellum. We measured postural sway (95% ellipse area of the center of pressure) during standing and CBI before iTBS and at multiple time points up to 30 min post-stimulation. Compared to sham, a single session of active iTBS reduced postural sway, with balance improvements sustained for at least 30 min post-stimulation. Cerebellar iTBS did not significantly alter CBI. Our results support the neuroplastic potential of the cerebellum as a viable target for therapeutic interventions aimed at improving balance in aging, potentially influencing circuits beyond direct cerebellar-M1 motor pathways.

Developing effective neuromodulation strategies for core autistic symptoms remains a critical need. The lateral cerebellum, implicated in socio-cognitive functions often affected in autism, represents a promising target for repetitive transcranial magnetic stimulation (rTMS), which has not yet been tested in this population. Here, we report a pilot investigation of the safety, feasibility, and network-level effects of one-session intermittent theta burst stimulation (iTBS, a variant of rTMS; 1200 pulses delivered at 80% active motor threshold with a 15-minute inter-train interval) targeting the right lateral cerebellum (Crus I/II) in 10 autistic adults (7 assigned male, 3 assigned female at birth, aged 19-30 years). All participants tolerated the protocol well, with no severe adverse events and a 100% retention rate. Resting-state functional MRI indicated a significant post-iTBS decrease in functional connectivity within the default-mode network and somatosensory motor network, while other networks remained unchanged. Moreover, idiosyncrasy in functional connectivity within the ventral attention, frontoparietal, default-mode and visual networks significantly decreased after iTBS. These findings suggest that cerebellar iTBS is safe and feasible for autistic adults and may acutely modulate multiple large-scale functional networks in their brain. Future multi-session, sham-controlled trials are warranted to validate these results and investigate whether repeated cerebellar stimulation yields sustained neurobiological or clinical benefits in autism.