The cerebellum and the Mirror Neuron System: a matter of inhibition? From neurophysiological evidence to neuromodulatory implications. A narrative review.

Mirror neurons show activity during both the execution (AE) and observation of actions (AO). The Mirror Neuron System (MNS) could be involved during motor imagery (MI) as well. Extensive research suggests that the cerebellum is interconnected with the MNS and may be critically involved in its activities. We gathered evidence on the cerebellum's role in MNS functions, both theoretically and experimentally. Evidence shows that the cerebellum plays a major role during AO and MI and that its lesions impair MNS functions likely because, by modulating the activity of cortical inhibitory interneurons with mirror properties, the cerebellum may contribute to visuomotor matching, which is fundamental for shaping mirror properties. Indeed, the cerebellum may strengthen sensory-motor patterns that minimise the discrepancy between predicted and actual outcome, both during AE and AO. Furthermore, through its connections with the hippocampus, the cerebellum might be involved in internal simulations of motor programs during MI. Finally, as cerebellar neuromodulation might improve its impact on MNS activity, we explored its potential neurophysiological and neurorehabilitation implications.

Horizontal Pendular Nystagmus and Ataxia Secondary to Severe Hypomagnesemia.

Background: Severe hypomagnesemia is an increasingly recognized cause of acute and reversible cerebellar ataxia, often accompanied by cerebellar oculomotor signs such as jerky horizontal or downbeat nystagmus and very rarely ocular flutter. Phenomenology Shown: This video illustrates horizontal pendular nystagmus in a patient with acute onset cerebellar ataxia associated with severe hypomagnesemia. Educational value: Acquired pendular nystagmus can be distinguished from macrosaccadic oscillations and ocular flutter in that the former is composed of two slow phases of equal velocity and the latter of two fast phases of saccadic type with or without intersaccadic interval, respectively. It is most commonly associated with demyelinating, toxic, metabolic, and genetic disorders, but has not been reported in association with severe hypomagnesemia.

Cerebellar nuclei cells produce distinct pathogenic spike signatures in mouse models of ataxia, dystonia, and tremor.

The cerebellum contributes to a diverse array of motor conditions, including ataxia, dystonia, and tremor. The neural substrates that encode this diversity are unclear. Here, we tested whether the neural spike activity of cerebellar output neurons is distinct between movement disorders with different impairments, generalizable across movement disorders with similar impairments, and capable of causing distinct movement impairments. Using in vivo awake recordings as input data, we trained a supervised classifier model to differentiate the spike parameters between mouse models for ataxia, dystonia, and tremor. The classifier model correctly assigned mouse phenotypes based on single-neuron signatures. Spike signatures were shared across etiologically distinct but phenotypically similar disease models. Mimicking these pathophysiological spike signatures with optogenetics induced the predicted motor impairments in otherwise healthy mice. These data show that distinct spike signatures promote the behavioral presentation of cerebellar diseases.

Intentional movement is fundamental to achieving many goals, whether they are as complicated as driving a car or as routine as feeding ourselves with a spoon. The cerebellum is a key brain area for coordinating such movement. Damage to this region can cause various movement disorders: ataxia (uncoordinated movement); dystonia (uncontrolled muscle contractions); and tremor (involuntary and rhythmic shaking). While abnormal electrical activity in the brain associated with movement disorders has been recorded for decades, previous studies often explored one movement disorder at a time. Therefore, it remained unclear whether the underlying brain activity is similar across movement disorders. Van der Heijden and Brown et al. analyzed recordings of neuron activity in the cerebellum of mice with movement disorders to create an activity profile for each disorder. The researchers then used machine learning to generate a classifier that could separate profiles associated with manifestations of ataxia, dystonia, and tremor based on unique features of their neural activity. The ability of the model to separate the three types of movement disorders indicates that abnormal movements can be distinguished based on neural activity patterns. When additional manifestations of these abnormal movements were considered, multiple mouse models of dystonia and tremor tended to show similar profiles. Ataxia models had several different types of neural activity that were all distinct from the dystonia and tremor profiles. After identifying the activity associated with each movement disorder, Van der Heijden and Brown et al. induced the same activity in the cerebella of healthy mice, which then caused the corresponding abnormal movements. These findings lay an important groundwork for the development of treatments for neurological disorders involving ataxia, dystonia, and tremor. They identify the cerebellum, and specific patterns of activity within it, as potential therapeutic targets. While the different activity profiles of ataxia may require more consideration, the neural activity associated with dystonia and tremor appears to be generalizable across multiple manifestations, suggesting potential treatments could be broadly applicable for these disorders.

A Comparative Study on Cognitive Assessment in Cerebellar and Supratentorial Stroke.

This study aims to understand the cognitive profiles of cerebellar infarction patients and compare them to those with supratentorial infarctions, particularly frontal infarctions. This current study also aims to find reliable assessment tools for detecting cognitive impairment in cerebellar infarction patients. A total of fifty cerebellar infarction patients, sixty supratentorial infarction patients, and thirty-nine healthy controls were recruited. The Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Addenbrooke's Cognitive Examination III (ACE-III), and Cerebellar Cognitive Affective Syndrome scale (CCAS-s) were used to assess global cognitive function. An extensive neuropsychological assessment battery was also tested to evaluate the characteristics of each cognitive domain. To assess the features of cognitive function, a comprehensive neuropsychological evaluation tool was also utilized. The cerebral infarction patients demonstrated cognitive impairment comparable to those with frontal infarcts, notably characterized by disturbance in attention and executive function. However, the degree of cognitive impairment was comparatively milder in cerebellar infarction patients. Furthermore, the patients in the cerebellar group had worse scores in the ACE-III and CCAS-s compared to healthy controls. The two assessments also demonstrated a significant area under the curve values, indicating their effectiveness in distinguishing cognitive impairment in cerebellar infarctions. In conclusion, cognitive impairment in a cerebellar infarction resembles frontal lobe dysfunction but is generally mild. It can be accurately assessed using the ACE-III and CCAS-s scales.

Altered cerebellar effective connectivity in first-episode schizophrenia and long-term changes after treatment.

AIM: Cerebello-cortical functional dysconnectivity plays a key role in the pathology of schizophrenia (SZ). We aimed to investigate the changes in cerebello-cortical directional connectivity in patients with SZ. METHODS: A total of 180 drug-naïve patients with first-episode SZ (54 reassessed after 1 year of treatment) and 166 healthy controls (HCs) were included. Resting-state functional magnetic resonance imaging was used to perform Granger causal analysis, in which each of the nine cerebellar functional systems was defined as a seed. The observed effective connectivity (EC) alterations at baseline were further assessed at follow-up and were associated with changes in psychotic symptom. RESULTS: We observed increased bottom-up EC in first-episode SZ from the cerebellum to the cerebrum (e.g. from the cerebellar attention and cingulo-opercular systems to the bilateral angular gyri, and from the cerebellar cingulo-opercular system to the right inferior frontal gyrus). In contrast, decreased top-down EC in the first-episode SZ was mainly from the cerebrum to the cerebellum (e.g. from the right inferior temporal gyrus, left middle temporal gyrus, left putamen, and right angular gyrus to the cerebellar language system). After 1 year of antipsychotic treatment, information projections from the cerebrum to the cerebellum were partly restored and positively related to symptom remission. CONCLUSION: These findings suggest that decreased top-down EC during the acute phase of SZ may be a state-dependent alteration related to symptoms and medication. However, increased bottom-up EC may reflect a persistent pathological trait.

Zonisamide Ameliorated the Apoptosis and Inflammation in Cerebellar Tissue of Induced Alcohol Addiction Animal Model.

This study investigated the effects of zonisamide treatment on cerebellar tissues in an experimental alcohol addiction (AA) model and its potential mechanisms of action, particularly regarding apoptotic protease activating factor-1 (APAF-1) and tumor necrosis factor-alpha (TNF-α) expression. Thirty rats were divided into three groups: sham, ethanol (EtOH), and EtOH + zonisamide. AA was induced by administering 6 cc of EtOH orally every 8 h for 4 days. Zonisamide (100 mg/kg) was given to rats once daily before EtOH administration. Motor defects were evaluated using an open field maze. Serum TNF-α levels were measured from blood samples. Cerebellar sections were processed for histological examination and immunostained for APAF-1 and TNF-α. Protein interaction networks were constructed using Cytoscape, and functional annotations were performed with ShinyGO (version 0.80) software. The traveled area in the EtOH group was significantly reduced compared to the sham group (p = 0.0005). Rats in the EtOH + zonisamide group covered a larger area, with zonisamide treatment significantly improving locomotor ability compared to the EtOH group (p = 0.0463). Serum TNF-α levels were significantly elevated in the EtOH group compared to the sham group (p < 0.0001) and were significantly decreased in the EtOH + zonisamide group compared to the EtOH group (p = 0.0309). Regular cerebellar histological layers were observed in the sham group, while EtOH induction caused loss of cerebellar tissue integrity, neuronal degeneration, vascular dilatation and congestion, reduced myelin density, and neuropils in the EtOH group. Zonisamide treatment improved these pathologies, enhancing myelination and neuropil formation. Negative APAF-1 and TNF-α expressions were observed across cerebellar layers in the sham group. Due to EtOH toxicity, APAF-1 and TNF-α expression were upregulated in the EtOH group compared to the sham group (p < 0.001 for both). Zonisamide treatment downregulated these protein expressions in the EtOH + zonisamide group compared to the EtOH group (p < 0.001 and p = 0.0087, respectively). APAF-1 was primarily associated with AA through antifolate resistance, endopeptidases, and the interleukin-1 pathway, while TNF-α was predominantly enriched in infections and choline-binding, indicating zonisamide's impact on immune and inflammatory pathways. In conclusion, zonisamide treatment significantly mitigated ethanol-induced cerebellar damage and inflammation in an AA model. Zonisamide improved locomotor function and reduced serum TNF-α levels, as well as APAF-1 and TNF-α expression in cerebellar tissues. These findings suggest that zonisamide exerts its protective effects by modulating immune and inflammatory pathways, thereby preserving cerebellar integrity and function.

Cerebellar Non-Invasive Brain Stimulation: A Frontier in Chronic Pain Therapy.

Chronic pain poses a widespread and distressing challenge; it can be resistant to conventional therapies, often having significant side effects. Non-invasive brain stimulation (NIBS) techniques offer promising avenues for the safe and swift modulation of brain excitability. NIBS approaches for chronic pain management targeting the primary motor area have yielded variable outcomes. Recently, the cerebellum has emerged as a pivotal hub in human pain processing; however, the clinical application of cerebellar NIBS in chronic pain treatment remains limited. This review delineates the cerebellum's role in pain modulation, recent advancements in NIBS for cerebellar activity modulation, and novel biomarkers for assessing cerebellar function in humans. Despite notable progress in NIBS techniques and cerebellar activity assessment, studies targeting cerebellar NIBS for chronic pain treatment are limited in number. Nevertheless, positive outcomes in pain alleviation have been reported with cerebellar anodal transcranial direct current stimulation. Our review underscores the potential for further integration between cerebellar NIBS and non-invasive assessments of cerebellar function to advance chronic pain treatment strategies.

No Additional Effects of Sequential Facilitatory Cerebral and Cerebellar rTMS in Subacute Stroke Patients.

The aim of this study was to investigate the additional effects of cerebellar rTMS on the motor recovery of facilitatory rTMS over affected primary motor cortex (M1) in subacute stroke patients. Twenty-eight subacute stroke patients were recruited in this single-blind, randomized, controlled trial. The Cr-Cbll group received Cr-Cbll rTMS stimulation consisting of high-frequency rTMS over affected M1 (10 min), motor training (10 min), and high-frequency rTMS over contralesional Cbll (10 min). The Cr-sham group received sham rTMS instead of high-frequency rTMS over the cerebellum. Ten daily sessions were performed for 2 weeks. A Fugl-Meyer Assessment (FMA) was measured before (T0), immediately after (T1), and 2 months after the intervention (T2). A total of 20 participants (10 in the Cr-Cbll group and 10 in the Cr-sham group) completed the intervention. There was no significant difference in clinical characteristics between the two groups at T0. FMA was significantly improved after the intervention in both Cr-Cbll and Cr-sham groups (p < 0.05). However, there was no significant interaction in FMA between time and group. In conclusion, these results could not demonstrate that rTMS over the contralesional cerebellum has additional effects to facilitatory rTMS over the affected M1 for improving motor function in subacute stroke patients.

Unravelling the Cerebellar Involvement in Autism Spectrum Disorders: Insights into Genetic Mechanisms and Developmental Pathways.

Autism spectrum disorders (ASDs) are complex neurodevelopmental conditions characterized by deficits in social interaction and communication, as well as repetitive behaviors. Although the etiology of ASD is multifactorial, with both genetic and environmental factors contributing to its development, a strong genetic basis is widely recognized. Recent research has identified numerous genetic mutations and genomic rearrangements associated with ASD-characterizing genes involved in brain development. Alterations in developmental programs are particularly harmful during critical periods of brain development. Notably, studies have indicated that genetic disruptions occurring during the second trimester of pregnancy affect cortical development, while disturbances in the perinatal and early postnatal period affect cerebellar development. The developmental defects must be viewed in the context of the role of the cerebellum in cognitive processes, which is now well established. The present review emphasizes the genetic complexity and neuropathological mechanisms underlying ASD and aims to provide insights into the cerebellar involvement in the disorder, focusing on recent advances in the molecular landscape governing its development in humans. Furthermore, we highlight when and in which cerebellar neurons the ASD-associated genes may play a role in the development of cortico-cerebellar circuits. Finally, we discuss improvements in protocols for generating cerebellar organoids to recapitulate the long period of development and maturation of this organ. These models, if generated from patient-induced pluripotent stem cells (iPSC), could provide a valuable approach to elucidate the contribution of defective genes to ASD pathology and inform diagnostic and therapeutic strategies.

Kainate receptors regulate synaptic integrity and plasticity by forming a complex with synaptic organizers in the cerebellum.

Kainate (KA)-type glutamate receptors (KARs) are implicated in various neuropsychiatric and neurological disorders through their ionotropic and metabotropic actions. However, compared to AMPA- and NMDA-type receptor functions, many aspects of KAR biology remain incompletely understood. Our study demonstrates an important role of KARs in organizing climbing fiber (CF)-Purkinje cell (PC) synapses and synaptic plasticity in the cerebellum, independently of their ion channel or metabotropic functions. The amino-terminal domain (ATD) of the GluK4 KAR subunit binds to C1ql1, provided by CFs, and associates with Bai3, an adhesion-type G protein-coupled receptor expressed in PC dendrites. Mice lacking GluK4 exhibit no KAR-mediated responses, reduced C1ql1 and Bai3 levels, and fewer CF-PC synapses, along with impaired long-term depression and oculomotor learning. Remarkably, introduction of the ATD of GluK4 significantly improves all these phenotypes. These findings demonstrate that KARs act as synaptic scaffolds, orchestrating synapses by forming a KAR-C1ql1-Bai3 complex in the cerebellum.

Identification of schizophrenia by applying interpretable radiomics modeling with structural magnetic resonance imaging of the cerebellum.

AIMS: The cerebellum is involved in higher-order mental processing as well as sensorimotor functions. Although structural abnormalities in the cerebellum have been demonstrated in schizophrenia, neuroimaging techniques are not yet applicable to identify them given the lack of biomarkers. We aimed to develop a robust diagnostic model for schizophrenia using radiomic features from T1-weighted magnetic resonance imaging (T1-MRI) of the cerebellum. METHODS: A total of 336 participants (174 schizophrenia; 162 healthy controls [HCs]) were allocated to training (122 schizophrenia; 115 HCs) and test (52 schizophrenia; 47 HCs) cohorts. We obtained 2568 radiomic features from T1-MRI of the cerebellar subregions. After feature selection, a light gradient boosting machine classifier was trained. The discrimination and calibration of the model were evaluated. SHapley Additive exPlanations (SHAP) was applied to determine model interpretability. RESULTS: We identified 17 radiomic features to differentiate participants with schizophrenia from HCs. In the test cohort, the radiomics model had an area under the curve, accuracy, sensitivity, and specificity of 0.89 (95% confidence interval: 0.82-0.95), 78.8%, 88.5%, and 75.4%, respectively. The model explanation by SHAP suggested that the second-order size zone non-uniformity feature from the right lobule IX and first-order energy feature from the right lobules V and VI were highly associated with the risk of schizophrenia. CONCLUSION: The radiomics model focused on the cerebellum demonstrates robustness in diagnosing schizophrenia. Our results suggest that microcircuit disruption in the posterior cerebellum is a disease-defining feature of schizophrenia, and radiomics modeling has potential for supporting biomarker-based decision-making in clinical practice.

The neural network of sensory attenuation: A neuroimaging meta-analysis.

Sensory attenuation refers to the reduction in sensory intensity resulting from self-initiated actions compared to stimuli initiated externally. A classic example is scratching oneself without feeling itchy. This phenomenon extends across various sensory modalities, including visual, auditory, somatosensory, and nociceptive stimuli. The internal forward model proposes that during voluntary actions, an efferent copy of the action command is sent out to predict sensory feedback. This predicted sensory feedback is then compared with the actual sensory feedback, leading to the suppression or reduction of sensory stimuli originating from self-initiated actions. To further elucidate the neural mechanisms underlying sensory attenuation effect, we conducted an extensive meta-analysis of functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) studies. Utilizing activation likelihood estimation (ALE) analysis, our results revealed significant activations in a prominent cluster encompassing the right superior temporal gyrus (rSTG), right middle temporal gyrus (rMTG), and right insula when comparing external-generated with self-generated conditions. Additionally, significant activation was observed in the right anterior cerebellum when comparing self-generated to external-generated conditions. Further analysis using meta-analytic connectivity modeling (MACM) unveiled distinct brain networks co-activated with the rMTG and right cerebellum, respectively. Based on these findings, we propose that sensory attenuation arises from the suppression of reflexive inputs elicited by self-initiated actions through the internal forward modeling of a cerebellum-centered action prediction network, enabling the "sensory conflict detection" regions to effectively discriminate between inputs resulting from self-induced actions and those originating externally.

Reliability and validity study of the Chinese version of the Cerebellar Cognitive Affective Syndrome Scale in patients with cerebellar injury.

PURPOSE: To preliminarily investigate the reliability and validity of the Chinese version of the Cerebellar Cognitive Affective Syndrome Scale (CCAS scale) in the cerebellar injury population. METHODS: In this study, 40 patients with cerebellar injury and 39 normal individuals hospitalized in a stroke center were assessed using the Chinese version of the CCAS scale A, MMSE, and PHQ2, and the results were analyzed using content validity, structural validity, internal consistency, inter- rater agreement, and test-retest reliability. RESULTS: The correlation coefficients of semantic fluency, phonemic fluency, category switching, digit span forward, digit span backward, cube, verbal recall, similarities and Go No-Go subscores in the Chinese version of the CCAS scale A were 0.586-0.831 (P ≤ 0.05) with the total score, but there was no significant correlation between the affect and the total score (P = 0.110). The total cognitive score of the Chinese version of the CCAS scale A was correlated with the (r = 0.807, P ≤ 0.01), and the total score of the Chinese version of the CCAS scale A affect was correlated with the total score of PHQ2 (r = 0.884, P ≤ 0.01). The 2 factors were extracted using principal component analysis, and the cumulative variance contribution rate was 59.633%. The factor loadings of each of the corresponding factors were > 0.5, indicating good structural validity of the Chinese version of the CCAS scale A. Cronbach α = 0.827 indicated good internal consistency, and inter-rater reliability (ICC > 0.95) and test-retest reliability (ICC = 0.717-0.895)indicated that the Chinese version of the CCAS scale A had good inter-rater reliability and test-retest reliability. CONCLUSION: The Chinese version of the CCAS scale A has good reliability and validity in the cerebellar injury population and is useful for screening cerebellar cognitive-emotional syndrome.

Cerebellar functional connectivity relates to lower urinary tract function: A 7 Tesla study.

OBJECTIVES: The objective of this study is to explore the functional connectivity (FC) of the cerebellum during the storage phase of micturition, through detecting spontaneous blood-oxygen-level dependent signal between the cerebellum and different brain regions using a high-resolution 7 Tesla magnetic resonance imaging (MRI) scanner. MATERIALS AND METHODS: We recruited healthy individuals with no reported history of neurological disease or lower urinary tract (LUT) symptoms. Participants were asked to drink 500 mL of water and then empty their bladders before entering the MRI scanner. They underwent a T1-weighted anatomical scan, followed by an initial (8 min) empty bladder resting state functional MRI (rs-fMRI) acquisition. Once subjects felt the desire to void, a second rs-fMRI scan was obtained, this time with a full bladder state. We established a priori cerebellar regions of interest from the literature to perform seed-to-voxel analysis using nonparametric statistics based on the Threshold Free Cluster Enhancement method and utilized a voxel threshold of p < 0.05. RESULTS: Twenty individuals (10 male and 10 female) with a median age of 25 years (IQR [3.5]) participated in the study. We placed 31 different 4-mm spherical seeds throughout the cerebellum and assessed their FC with the remainder of the brain. Three of these (left cerebellar tonsil, right posterolateral lobe, right posterior lobe) showed significant differences in connectivity when comparing scans conducted with a full bladder to those with an empty bladder. Additionally, we observed sex differences in FC, with connectivity being higher in women during the empty bladder condition. CONCLUSION: Our initial findings reveal, for the first time, that the connectivity of the cerebellar network is modulated by bladder filling and is associated with LUT function. Unraveling the cerebellum's role in bladder function lays the foundation for a more comprehensive understanding of urinary pathologies affecting this area.

The cerebellum: the 'little' brain and its big role.

Reports from recent years provide compelling evidence about the structure and the existence of functional topography in the cerebellum. However, most of them focused on the motor functions of the cerebellum. Recent studies suggest the involvement of the posterior lobe of the cerebellum in the context of neurodegenerative and cognitive disorders. The pathophysiology of these diseases is not sufficiently understood, and recent studies indicate that it could also affect additional subregions of the cerebellum. Anatomical and clinical studies, combined with neuroimaging, provide new ways of thinking about the organization and functioning of the cerebellum. This review summarizes knowledge about the topography and functions of the cerebellum, and focuses on its anatomical and functional contributions to the development of neurological diseases.

Morphological characteristics of cerebellum, pons and thalamus in Reccurent isolated sleep paralysis - A pilot study.

Introduction: Recurrent isolated sleep paralysis (RISP) is a rapid eye movement sleep (REM) parasomnia, characterized by the loss of voluntary movements upon sleep onset and/or awakening with preserved consciousness. Evidence suggests microstructural changes of sleep in RISP, although the mechanism of this difference has not been clarified yet. Our research aims to identify potential morphological changes in the brain that can reflect these regulations. Materials and methods: We recruited 10 participants with RISP (8 women; mean age 24.7 years; SD 2.4) and 10 healthy control subjects (w/o RISP; 3 women; mean age 26.3 years; SD 3.7). They underwent video-polysomnography (vPSG) and sleep macrostructure was analyzed. After that participants underwent magnetic resonance imaging (MRI) of the brain. We focused on 2-dimensional measurements of cerebellum, pons and thalamus. Statistical analysis was done in SPSS program. After analysis for normality we performed Mann-Whitney U test to compare our data. Results: We did not find any statistically significant difference in sleep macrostructure between patients with and w/o RISP. No evidence of other sleep disturbances was found. 2-dimensional MRI measurements revealed statistically significant increase in cerebellar vermis height (p = 0.044) and antero-posterior diameter of midbrain-pons junction (p = 0.018) in RISP compared to w/o RISP. Discussion: Our results suggest increase in size of cerebellum and midbrain-pons junction in RISP. This enlargement could be a sign of an over-compensatory mechanism to otherwise dysfunctional regulatory pathways. Further research should be done to measure these differences in time and with closer respect to the frequency of RISP episodes.

Efficacy of Cerebellar Transcranial Magnetic Stimulation in Treating Essential Tremor: A Randomized, Sham-Controlled Trial.

BACKGROUND AND PURPOSE: Repetitive transcranial magnetic stimulation (rTMS) of the cerebellar hemisphere represents a new option in treating essential tremor (ET) patients. We aimed to determine the efficacy of cerebellar rTMS in treating ET using different protocols regarding the number of sessions, exposure duration, and follow-up duration. METHODS: A randomized sham-controlled trial was conducted, in which 45 recruit patients were randomly allocated to 2 groups. The first (active group) comprised 23 patients who were exposed to 12 sessions of active rTMS with 900 pulses of 1-Hz rTMS at 90% of the resting motor threshold daily on each side of the cerebellar hemispheres over 4 weeks. The second group (sham group) comprised 22 patients who were exposed to 12 sessions of sham rTMS. Both groups were reassessed at baseline and after 1 day, 1 month, 2 months, and 3 months using the Fahn-Tolosa-Marin tremor-rating scale (FTM). RESULTS: Demographic characteristics did no differ between the two groups. There were significant reductions both in FTM subscores A and B and in the FTM total score in the active-rTMS group during the period of assessment and after 3 months (p=0.031 and 0.011, respectively). However, subscore C did not change significantly from baseline when assessed at 2 and 3 months (p=0.073 and 0.236, respectively). Furthermore, the global assessment score was significantly higher in the active-rTMS group (p>0.001). CONCLUSIONS: Low-frequency rTMS over the cerebellar cortex for 1 month showed relative safety and long-lasting efficacy in patients with ET. Further large-sample clinical trials are needed that include different sites of stimulation and longer follow-ups.

Neuroanatomy of cerebellar mutism syndrome: the role of lesion location.

Approximately 25% of paediatric patients who undergo cerebellar tumour resection develop cerebellar mutism syndrome. Our group recently showed that damage to the cerebellar deep nuclei and superior cerebellar peduncles, which we refer to as the cerebellar outflow pathway, is associated with an increased risk of cerebellar mutism syndrome. Here, we tested whether these findings replicate in an independent cohort. We evaluated the relationship between lesion location and the development of cerebellar mutism syndrome in an observational study of 56 paediatric patients ranging from five months to 14 years of age who underwent cerebellar tumour resection. We hypothesized that individuals who developed cerebellar mutism syndrome after surgery, relative to those who did not, would have lesions that preferentially intersect with: (i) the cerebellar outflow pathway and (ii) a previously generated 'lesion-symptom map' of cerebellar mutism syndrome. Analyses were conducted in accordance with pre-registered hypotheses and analytic methods (https://osf.io/r8yjv/). We found supporting evidence for both hypotheses. Compared to patients who did not develop cerebellar mutism syndrome, patients with cerebellar mutism syndrome (n = 10) had lesions with greater overlap with the cerebellar outflow pathway (Cohen's d = 0.73, P = 0.05), and the cerebellar mutism syndrome lesion-symptom map (Cohen's d = 1.1, P = 0.004). These results strengthen the association of lesion location with the risk of developing cerebellar mutism syndrome and demonstrate generalizability across cohorts. These findings may help to inform the optimal surgical approach to paediatric cerebellar tumours.

Alcohol Toxicity in the Developing Cerebellum.

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.

Prosopis africana exerts neuroprotective activity against quaternary metal mixture-induced memory impairment mediated by oxido-inflammatory response via Nrf2 pathway.

The beneficial effects of Prosopis africana (PA) on human health have been demonstrated; however, its protective effects against heavy metals (HM) are not yet understood. This study evaluated the potential neuroprotective effects of PA in the cerebral cortex and cerebellum. To accomplish this, we divided 35 albino Sprague Dawley rats into five groups. Group I did not receive either heavy metal mixture (HMM) or PA. Group II received a HMM of PbCl2 (20 mg/kg), CdCl2 (1.61 mg/kg), HgCl2 (0.40 mg/kg), and NaAsO3 (10 mg/kg) orally for a period of two months. Groups III, IV, and V received HMM along with PA at doses of 500, 1000, and 1500 mg/kg, respectively. PA caused decreased levels of HM accumulation in the cerebral cortex and cerebellum and improved performance in the Barnes maze and rotarod tests. PA significantly reduced levels of IL-6 and TNF-α. PA increased concentrations of SOD, CAT, GSH, and Hmox-1 and decreased the activities of AChE and Nrf2. In addition, levels of MDA and NO decreased in groups III, IV, and V, along with an increase in the number of live neurons. In conclusion, PA demonstrates a complex neuroprotective effect with the potential to alleviate various aspects of HM-induced neurotoxicity.