Cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) and disease spectrum is an autosomal recessive disorder associated with biallelic repeat expansion (RE) in the RFC1 gene. A high carrier frequency in the healthy population determines the possibility of having affected members in two consecutive generations. We describe pseudodominance in two families affected with RFC1 disorder (10 affected, 5 oligo/asymptomatic individuals). In Family A, after the 75-year-old index case was diagnosed with CANVAS, the 73-year-old wife decided to undergo screening for carrier testing. Although she did not report any symptoms, she resulted positive for the biallelic AAGGG RE thus leading to a diagnosis in the asymptomatic offspring as well and revealing a pseudodominant pattern of inheritance. In Family B pseudodominance was suspected after the identification of the RFC1 RE in the proband affected by sensitive neuropathy because of a positive family history for undetermined polyneuropathy in the mother. The post-mortem identification of the RFC1 RE in a sample specimen from the deceased mother, who had been under our care, allowed the solution of a "cold case". Our report suggests that pseudodominance is a confounding phenomenon to consider in RFC1-spectrum disorder and genetic counselling is instrumental in families with affected individuals.

Rhombencephalosynapsis (RES) is a hindbrain malformation characterized by a missing cerebellar vermis with apposition or fusion of the cerebellar hemispheres. The present clinical case report provides a comprehensive, longitudinal overview of cognitive and affective manifestations in a 22-year-old patient with RES. The patient shows clinical signs of emotional reactivity and dysregulation, impulsivity, and impairments in executive functioning since early childhood. These features fit the constellation of neuropsychiatric symptoms observed in patients with congenital and acquired abnormalities of the posterior vermis. It is proposed that patients with RES may show affective and cognitive difficulties which increase their vulnerability to psychological stress and risk of developing mental health issues.

The emotional and cognitive cerebellum has been explored by several studies in the past years. Recent evidence suggested the possible contribution of the cerebellum in processing emotional prosody, namely the ability to comprehend the emotional content of a given vocal utterance, likely mediated by anatomical and functional cerebello-prefrontal connections. In the present study, the involvement of a functional cerebello-prefrontal network in recognising emotional prosody was assessed by combining non-invasive anodal transcranial direct current stimulation (tDCS) over the right or the left cerebellum and functional Near Infrared Spectroscopy of the prefrontal cortex, in a double-blind within-subject experimental design on healthy participants. The results showed that right and, to a less extent, left cerebellar tDCS (as compared to sham stimulation) reduced neural activation in the prefrontal cortex while accuracy and reaction times at the vocal recognition task remained unchanged. These findings highlight functional properties of the cerebello-frontal connections and the psychophysiological effects of cerebellar brain stimulation, with possible clinical applications in psychiatric and neurological conditions.

Spinocerebellar ataxia (SCA) is an autosomal dominant hereditary disease with a low prevalence, for which more than 50 types have been described. This group of neurodegenerative diseases can present as different phenotypes with varying progression rates and clinical manifestations of different severities. Herein, we systematically reviewed existing medical literature to describe the main characteristics of polyneuropathy in patients with SCA types 2, 3, and 10. Using relevant keywords, 16,972 articles were identified from the databases. Of these, 5,329 duplicate studies were excluded before screening. Subsequently, 11,643 studies underwent title and abstract review, of which only 49 were selected for full-text review. Among these, 24 studies were included. The medical literature suggests peripheral neuropathy - probably in a polyneuropathy phenotype - in SCA types 2 and 3. It is not possible to determine whether there is peripheral neuropathy in patients with SCA type 10, as there is only one case series in Mexico that described peripheral neuropathy in this group. Further studies are required to investigate peripheral neuropathy in patients with SCA types 2, 3, and 10. The study and description of a possible statistical association between CAG repeats and SARA scale scores with the presence of peripheral neuropathy are important points requiring assessment in future research.

Ataxia telangiectasia (AT), Louis-Bar syndrome, is a rare neurodegenerative disorder caused by autosomal recessive biallelic mutations within the ataxia telangiectasia mutated (ATM) gene. Currently, there are no curative therapies available for this disorder. This review provides an overview of the latest advances in treatment methods including 1- Acetyl-DL-leucine, 2- Bone Marrow Transplantation, 3- Gene Therapy, 4- Dexamethasone, and finally 5- Red Blood Cells (RBCs) as a carrier for dexamethasone (encapsulation of dexamethasone sodium phosphate into autologous erythrocytes, known as EryDex). Most of the treatments under investigation are in the early stages, except for the EryDex System. It appears that the EryDex system and N-Acetyl-DL-Leucine may hold promise as potential treatment options.

Recent functional MRI studies have implicated the cerebellum in working memory (WM) alongside the prefrontal cortex. Some findings indicate that the right cerebellum is activated during verbal tasks, while the left is engaged during visuospatial tasks, suggesting cerebellar lateralization in WM function. The cerebellum could be a potential target for non-invasive brain stimulation (NIBS) to enhance WM function in cognitive disorders. However, the comprehensive influence of cerebellar lateralization on different types of WM and the effect of stimulation over the unilateral or bilateral cerebellum remain uncertain. This study was to investigate the cerebellum's functional lateralization and its specific impact on various aspects of WM in a causal manner using unilateral or bilateral cerebellar continuous theta burst stimulation (cTBS), a form of inhibitroy NIBS. Twenty-four healthy participants underwent four sessions of cTBS targeting the left, right, or bilateral Crus I of the cerebellum, or a sham condition, in a controlled cross-over design. WM performance was assessed pre- and post-stimulation using neuropsychological tests, including the 3-back task, spatial WM task, and digit span task. Results indicated that cTBS over the bilateral and right cerebellum both led to a greater improvement in 3-back task performance compared to sham stimulation. Additionally, active cTBS over the bilateral cerebellum yielded better performance in the spatial WM task than sham stimulation. However, no significant differences were observed between stimulation conditions for the auditory digit span task. This study may provide novel causal evidence highlighting the specific involvement of the right and bilateral cerebellum in various types of WM. Specifically, the right cerebellum appears crucial for updating and tracking 3-back WM content, while spatial WM processes require the coordinated engagement of both cerebellar hemispheres.

Multiple system atrophy-cerebellar type (MSA-C) exhibits faster disease progression than does hereditary spinocerebellar degeneration (hSCD). In this study, we aimed to investigate the differences in the treatment effects and sustainability of intensive rehabilitation between patients with hSCD and those with MSA-C. Forty-nine patients (hSCD = 30, MSA-C = 19) underwent a 2- or 4-week intensive rehabilitation program. Balance function was evaluated using the scale for the assessment and rating of ataxia (SARA) and the balance evaluation systems test (BESTest) at pre-intervention, post-intervention, and 6-month follow-up. Notably, both groups demonstrated beneficial effects from the rehabilitation intervention. However, differences were observed in the magnitude and duration of these effects. In the hSCD group, the SARA scores at follow-up remained similar to those at baseline, indicating sustained benefits. However, the MSA-C group showed some deterioration in SARA scores compared with baseline scores but maintained improvements on the BESTest, demonstrating partial sustainability. Differences, mainly in sustainability, were observed between the hSCD and MSA-C groups. This may be due to varying rates of symptom progression. The findings of this study are significant when considering the frequency of follow-ups based on disease type.

Silica nanoparticles (SiNPs) have been touted for their role in the management of non-communicable diseases. Their neuroprotective benefits against heavy metal-induced neurotoxicity remain largely unexplored. This is a comparative evaluation of the oxido-inflammatory and neurotrophic effects of Ni, Al, and Ni/Al mixture on the cerebellum of male albino rats with or without treatment with SiNPs generated from melon seed husk. The study complied with the ARRIVE guidelines for reporting in vivo experiments. A total of 91, 7-9 week-old weight-matched male Sprague rats (to avoid sex bias) were randomly divided into 13 different dosing groups where Group 1 served as the control. Other groups received 0.2 mg/kg Ni, 1 mg/kg Al, and 0.2 mg/kg Ni + 1 mg/kg Al mixture with or without different doses of SiNP for 90 days. Rotarod performance was carried out. Oxidative stress markers, Ni, Al, Ca, Fe, Mg, neurotrophic factors, amyloid beta (Aβ-42), cyclooxygenase-2 (COX-2), and acetylcholinesterase (AChE) were determined in the cerebellum. SiNPs from melon seed husk caused a significant decrease in Aβ-42 level and activities of AChE and COX-2 and a significant increase in brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) mediated by Ni, Al, and Ni/Al mixture exposure in rats. Neurotoxicity of the Ni/Al mixture is via heightened neuronal lipoperoxidative damage, decreased Mg, and increased Fe, and co-administration of SiNPs from melon seed husk with the Ni/Al mixture attenuated some of these biochemical changes in the cerebellum.

Cerebellar transcranial direct current stimulation (ctDCS) has emerged as a promising, non-invasive, and safe neuromodulatory intervention capable of reducing ataxia symptoms and restoring cerebellum-motor connectivity. However, previous studies have only applied ctDCS in isolation, without association with specific training. This study aimed to assess the effect of ctDCS combined with gait training on functional mobility, balance, and symptoms and severity of ataxia. A randomized, triple-blind, sham-controlled, bi-center clinical trial was conducted with forty-four adults with cerebellar ataxia. Volunteers were randomized to receive five daily sessions of either real ctDCS (n = 11; 2 mA for 25 min) or sham ctDCS (n = 11) during gait training. Functional mobility, balance, and symptoms and severity of ataxia were assessed using the Time Up and Go test, the MiniBESTest, and the Scale for the Assessment and Rating of Ataxia (SARA), respectively, before and after the interventions. Both groups showed improvement in functional mobility, but there was no significant difference between the ctDCS and sham groups. However, the ctDCS group demonstrated significant improvements in cerebellar ataxia severity as reflected by SARA scores, particularly in tests of stance, sitting, speech disturbance, nose-finger test, and heel-shin slide test. Notably, no improvements were observed in balance. This study indicates that while ctDCS combined with gait training may improve specific symptoms of cerebellar ataxia, it does not significantly enhance overall functional mobility compared to sham treatment.

Cerebellar transcranial direct current stimulation (tDCS) has been shown to influence movement functions, but little is known about the specific effects of stimulation polarity on balance control. This study investigated the impact of bilateral cerebellar tDCS on balance functions as a function of stimulation polarity. In this randomized, controlled trial, thirty-nine healthy young adults were assigned to one of three groups: right anodal/left cathodal cerebellar stimulation (AC group), right cathodal/left anodal cerebellar stimulation (CA group), and a control sham group. Each participant underwent a daily 30-minute session of tDCS at 2 mA for one week. Balance function was assessed pre- and post-intervention and the data were analyzed using generalized estimating equations. The CA group exhibited a significant reduction in sway area when standing on the left leg and on both stable and unstable surfaces with eyes open, compared to both the AC and sham groups. However, there were no significant differences among the groups in terms of sway length, anteroposterior velocity, or mediolateral velocity. Our results indicate the polarity-dependent effects of bilateral cerebellar tDCS on balance functions, with enhanced stability observed only following cathodal tDCS over the right cerebellum paired with anodal tDCS over the left cerebellum. This polarity-specific modulation may have implications for developing cerebellar neuromodulation interventions for movement disorders.

In the past few years, SARS-CoV-2 infection has substantially impacted public health. Alongside respiratory symptoms, some individuals have reported new neurological manifestations or a worsening of pre-existing neurological conditions. We previously documented two cases of essential tremor (ET) who experienced a deterioration in tremor following SARS-CoV-2 infection. However, the effects of SARS-CoV-2 on ET remain largely unexplored. This study aims to evaluate the impact of SARS-CoV-2 infection on a relatively broad sample of ET patients by retrospectively comparing their clinical and kinematic data collected before and after the exposure to SARS-CoV-2. We surveyed to evaluate the impact of SARS-CoV-2 infection on tremor features in ET. Subsequently, we retrospectively analysed clinical and kinematic data, including accelerometric recordings of postural and kinetic tremor. We included 36 ET patients (14 females with a mean age of 71.1 ± 10.6 years). Among the 25 patients who reported SARS-CoV-2 infection, 11 (44%) noted a subjective worsening of tremor. All patients reporting subjective tremor worsening also exhibited symptoms of long COVID, whereas the prevalence of these symptoms was lower (50%) in those without subjective exacerbation. The retrospective analysis of clinical data revealed a tremor deterioration in infected patients, which was not observed in non-infected patients. Finally, kinematic analysis revealed substantial stability of tremor features in both groups. The study highlighted a potential correlation between the SARS-CoV-2 infection and clinical worsening of ET. Long COVID contributes to a greater impact of tremor on the daily life of ET patients.

Under stress, Purkinje cells (PCs) undergo a variety of reactive morphological changes. These can include swellings of neuronal processes. While axonal swellings, "torpedoes", have been well-studied, dendritic swellings (DS) have not been the centerpiece of study. Surprisingly little is known about their frequency or relationship to other morphological changes in degenerating PCs. Leveraging a large brain bank, we (1) examined the morphology of DS, (2) quantified DS, and (2) examined correlations between counts of DS versus 16 other PC morphological changes in a broad range of cerebellar degenerative disorders. There were 159 brains - 100 essential tremor (ET), 13 Friedreich's ataxia, and 46 spinocerebellar ataxia (SCA) (14 SCA1, 7 SCA2, 13 SCA3, 5 SCA6, 5 SCA7, and 2 SCA8). DS were a feature of PCs across all these disorders, with varying morphologies and changes elsewhere in the dendritic arbor. On Luxol fast blue/hematoxylin and eosin-stained sections, the median number of DS per PC ranged from 0.001 in ET to 0.025 in SCA8. Bielschowsky-stained sections yielded higher counts, from 0.003 in ET to 0.042 in SCA6. Torpedo counts exceeded DS counts by one order of magnitude. DS counts were more robustly correlated with torpedo counts than with counts for any of the other PC morphological changes. In summary, DS ranged in prevalence across cerebellar degenerative disorders, from 1/1,000 to 42/1,000 PCs. Across disorders of cerebellar degeneration, these swellings of the dendritic compartment were most robustly correlated with swellings of the axonal compartment, suggesting a similar type of cellular response to duress.

Spinocerebellar ataxias (SCAs) are a diverse group of hereditary neurodegenerative disorders characterized by progressive degeneration of the cerebellum and other parts of the nervous system. In this study, we examined the genotype‒phenotype correlations in SCAs within the Brazilian population by leveraging a comprehensive dataset of 763 individuals from SARAH Network of Rehabilitation Hospitals. Using a retrospective, cross-sectional, observational, multicentric approach, we analysed medical records and conducted standardized molecular testing to explore epidemiological characteristics, clinical manifestations, and genetic profiles of SCAs in Brazil. Our findings revealed the predominance of SCA3, followed by SCA7 and SCA2, which aligns with global trends and reflects the specific genetic landscape of Brazil. A significant inverse relationship between the age of symptom onset and CAG repeat length in the mutated allele was observed across SCAs 2, 3, and 7. This study also highlights a trend towards paternal inheritance in SCA2 and details the distribution of CAG repeat expansions, which correlates larger expansions with earlier onset and specific symptomatology. This extensive analysis underscores the critical importance of genetic testing in the diagnosis and management of SCAs and enlightens the intricate genotype‒phenotype interplay within a genetically diverse population. Despite certain limitations, such as potential selection bias and the retrospective nature of the study, our research provides invaluable insights into the prevalence, genetic underpinnings, and clinical variability of SCAs in Brazil. We suggest a broader demographic scope and investigations into nonmotor symptoms in future studies to obtain a more comprehensive understanding of SCAs.

Spontaneous cerebellar hemorrhage (SCH) patients have a low success rate in extubation, but there are currently no guidelines establishing specifically for SCH patients extubation. The study included 68 SCH patients who received mechanical ventilation for more than 24 h, with 39 cases (57.3%) resulting in successful extubation. The multivariate analysis identified four factors significantly associated with extubation success: patient age under 66 years, an Intracerebral Hemorrhage (ICH) score less than 4 points, the presence of tissue shift, and a Glasgow Coma Scale (GCS) score (excluding language) above 6 points at extubation. By simplifying the prediction model, we obtained the Spontaneous Cerebellar Hemorrhage Extubation Success scoring system (SCHES-SCORE). Within the scoring system, 2 points were allocated for a GCS score (excluding language) above 6 at extubation, 1 point each for age under 66 years and an ICH score below 4, while tissue shift was assigned a negative point. A score of Grade A (SCHES-SCORE = 3-4) was found to correlate with a 92.9% success rate for extubation. The area under the receiver operating characteristic curve was 0.923 (95% CI, 0.863 to 0.983). Notably, successful extubation was significantly linked to reduced durations of mechanical ventilation, intensive care unit (ICU) stay, and total hospital stay. In conclusion, the scoring system developed for assessing extubation outcomes in SCH patients has the potential to enhance the rate of successful extubation and overall patient outcomes.

Bi-allelic pathogenic variants in GRID2 have been initially associated to an autosomal recessive form of spinocerebellar ataxia, namely SCAR18. Subsequently, few monoallelic cases have been described. Here we present a new subject harboring a novel de novo heterozygous GRID2 missense variant presenting with progressive ataxia together with cerebellar atrophy and, for the first time, alpha-fetoprotein (AFP) elevation. We retrospectively collected data of the patient followed at our clinic. Genetic analysis was performed through clinical exome sequencing with an in-house in-silico ataxia-related genes panel. Variant effect prediction was performed through in silico modeling. The patient had normal psychomotor development except for mild fine and gross motor impairment. In adolescence, he started presenting dysarthria and progressive ataxia. Blood tests showed significant AFP elevation. Brain MRI showed cerebellar atrophy mainly involving the vermis. The novel de novo heterozygous GRID2 (c.1954C>A; p.Leu652Ile) missense variant was disclosed. This variant is located within a highly conserved site with low tolerance to variation and it is predicted to cause protein structure destabilization. GRID2 expression appears to be influenced by other genes related with ataxia and AFP elevation, like ATM and APTX, suggesting a possible shared mechanism. This additional patient increases the scarce literature and genotypic spectrum of the GRID2-related ataxia and evidences a fairly homogeneous phenotype of ataxia with oculomotor abnormalities for the autosomal-dominant form. Alfa-fetoprotein elevation is a novel finding in this condition and this data must be confirmed in larger case-series to definitively state that GRID2-related ataxia can be included among ataxias with AFP increase.

Fatty acids play many critical roles in brain function but have not been investigated in essential tremor (ET), a frequent movement disorder suspected to involve cerebellar dysfunction. Here, we report a postmortem comparative analysis of fatty acid profiles by gas chromatography in the cerebellar cortex from ET patients (n = 15), Parkinson's disease (PD) patients (n = 15) and Controls (n = 17). Phosphatidylcholine (PC), phosphatidylethanolamine (PE) and phosphatidylinositol (PI)/ phosphatidylserine (PS) were separated by thin-layer chromatography and analyzed separately. First, the total amounts of fatty acids retrieved from the cerebellar cortex were lower in ET patients compared with PD patients, including monounsaturated (MUFA) and polyunsaturated fatty acids (PUFA). The diagnosis of ET was associated with lower cerebellar levels of saturated fatty acids (SFA) and PUFA (DHA and ARA) in the PE fraction specifically, but with a higher relative content of dihomo-γ-linolenic acid (DGLA; 20:3 ω-6) in the PC fraction. In contrast, a diagnosis of PD was associated with higher absolute concentrations of SFA, MUFA and ω-6 PUFA in the PI + PS fractions. However, relative PI + PS contents of ω-6 PUFA were lower in both PD and ET patients. Finally, linear regression analyses showed that the ω-3:ω-6 PUFA ratio was positively associated with age of death, but inversely associated with insoluble α-synuclein. Although it remains unclear how these FA changes in the cerebellum are implicated in ET or PD pathophysiology, they may be related to an ongoing neurodegenerative process or to dietary intake differences. The present findings provide a window of opportunity for lipid-based therapeutic nutritional intervention.

Spinocerebellar ataxias (SCAs) are characterized by substantial phenotypic variability. Among them, SCA42 is a rare non-expansion entity presenting with slowly progressive cerebellar syndrome but whose clinical spectrum may be also wider. A 53-year-old male presented with progressive myoclonus-ataxia and intellectual disability. Genetic screening revealed a novel c.3835G > A (p. Asp1279Asn) variant in the CACNA1G gene. SCA42 is a rare non-expansion SCA caused by mutations in CACNA1G on chromosome 17q21, encoding the Ca(V)3.1, a low-threshold voltage-gated T-type calcium channel. The novel variant we identified is potentially involved in channel activity. This case expands the knowledge regarding CACNA1G-associated phenotype and highlights the importance of genetic screening in myoclonus-ataxia disorders.

Post-traumatic stress disorder (PTSD) is a debilitating mental health condition characterized by recurrent re-experiencing of traumatic events. Despite increasing evidence suggesting that the cerebellum is involved in PTSD pathophysiology, it remains unclear whether this involvement is related to symptoms directly resulting from previous trauma exposure, such as involuntary re-experiencing of the traumatic events, or reflects a broader cerebellar engagement in negative affective states. In this study, we investigated the specific role of the cerebellum in PTSD by employing a script reactivation paradigm with personalized traumatic and sad autobiographical memories in 28 individuals diagnosed with chronic PTSD. Functional magnetic resonance imaging (fMRI) data were collected while participants listened to their own autobiographical narratives recounted by a third person. Activation in the right cerebellar lobule VI was uniquely associated with traumatic autobiographical recall and was parametrically modulated by the severity of re-experiencing symptoms. In contrast, cerebellar Crus II showed increased activation during both traumatic and sad autobiographical recall, suggesting a broader involvement in processing negative emotions. Our findings highlight the unique contribution of the right cerebellar lobule VI in the processing of traumatic autobiographical memories, potentially through its engagement in low-level representation of sensory and emotional aspects of traumatic events.

Motor adaptation is critical to update motor tasks in new or modified environmental conditions. While the cerebellum supports error-based adaptations, its neural implementation is partially known. By controlling the frequency of cerebellar transcranial alternating current stimulation (c-tACS), we can test the influence of neural oscillation from the cerebellum for motor adaptation. Two independent experiments were conducted. In Experiment 1, 16 participants received four c-tACS protocols (45 Hz, 50 Hz, 55 Hz, and sham) on four different days while they practiced a visuomotor adaptation task (30 degrees CCW) with variable intensity (within-subject design). In Experiment 2, 45 participants separated into three groups received the effect of 45 Hz, 55 Hz c-tACS, and sham, respectively (between-subject design), performing the same visuomotor task with a fixed intensity (0.9 mA). In Experiment 1, 45 Hz and 50 Hz of c-tACS accelerated motor adaptation when participants performed the task only for the first time, independent of the time interval between sessions or the stimulation intensity. The effect of active c-tACS was ratified in Experiment 2, where 45 Hz c-tACS benefits motor adaptation during the complete practice period. Reaction time, velocity, or duration of reaching are not affected by c-tACS. Cerebellar alternating current stimulation is an effective strategy to potentiate visuomotor adaptations. Frequency-dependent effects on the gamma band, especially for 45 Hz c-tACS, ratify the oscillatory profile of cerebellar processes behind the motor adaptation. This can be exploited in future interventions to enhance motor learning.