Disentangling the Role of Gray Matter Volume and Concentration in Autism Spectrum Disorder: A Meta-Analytic Investigation of 25 Years of Voxel-Based Morphometry Research.

Despite over two decades of neuroimaging research, a unanimous definition of the pattern of structural variation associated with autism spectrum disorder (ASD) has yet to be found. One potential impeding issue could be the sometimes ambiguous use of measurements of variations in gray matter volumes (GMV) or gray matter concentrations (GMC). In fact, while both can be calculated using voxel-based morphometry analysis, these may reflect different underlying pathological mechanisms. We conducted a coordinate-based meta-analysis, keeping apart GMV and GMC studies of subjects with ASD. Results showed distinct and non-overlapping patterns for the two measures. GMV decreases were evident in the cerebellum, while GMC decreases were mainly found in the temporal and frontal regions. GMV increases were found in the parietal, temporal, and frontal brain regions, while GMC increases were observed in the anterior cingulate cortex and middle frontal gyrus. Age-stratified analyses suggested that such variations are dynamic across the ASD lifespan. The present findings emphasize the importance of considering GMV and GMC as distinct yet synergistic indices in autism research.

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.

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.

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.

Systemic pharmacological suppression of neural activity reverses learning impairment in a mouse model of Fragile X syndrome.

The enhancement of associative synaptic plasticity often results in impaired rather than enhanced learning. Previously, we proposed that such learning impairments can result from saturation of the plasticity mechanism (Nguyen-Vu et al., 2017), or, more generally, from a history-dependent change in the threshold for plasticity. This hypothesis was based on experimental results from mice lacking two class I major histocompatibility molecules, MHCI H2-Kb and H2-Db (MHCI KbDb-/-), which have enhanced associative long-term depression at the parallel fiber-Purkinje cell synapses in the cerebellum (PF-Purkinje cell LTD). Here, we extend this work by testing predictions of the threshold metaplasticity hypothesis in a second mouse line with enhanced PF-Purkinje cell LTD, the Fmr1 knockout mouse model of Fragile X syndrome (FXS). Mice lacking Fmr1 gene expression in cerebellar Purkinje cells (L7-Fmr1 KO) were selectively impaired on two oculomotor learning tasks in which PF-Purkinje cell LTD has been implicated, with no impairment on LTD-independent oculomotor learning tasks. Consistent with the threshold metaplasticity hypothesis, behavioral pre-training designed to reverse LTD at the PF-Purkinje cell synapses eliminated the oculomotor learning deficit in the L7-Fmr1 KO mice, as previously reported in MHCI KbDb-/-mice. In addition, diazepam treatment to suppress neural activity and thereby limit the induction of associative LTD during the pre-training period also eliminated the learning deficits in L7-Fmr1 KO mice. These results support the hypothesis that cerebellar LTD-dependent learning is governed by an experience-dependent sliding threshold for plasticity. An increased threshold for LTD in response to elevated neural activity would tend to oppose firing rate stability, but could serve to stabilize synaptic weights and recently acquired memories. The metaplasticity perspective could inform the development of new clinical approaches for addressing learning impairments in autism and other disorders of the nervous system.

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.

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.

The crucial role of the cerebellum in autism spectrum disorder: Neuroimaging, neurobiological, and anatomical insights.

Background and Aims: Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by a wide range of symptoms and challenges. While ASD is primarily associated with atypical social and communicative behaviors, increasing research has pointed towards the involvement of various brain regions, including the cerebellum. This review article aims to provide a comprehensive overview of the role of cerebellar lobules in ASD, highlighting recent findings and potential therapeutic implications. Methods: Using published articles found in PubMed, Scopus, and Google Scholar, we extracted pertinent data to complete this review work. We have searched for terms including anatomical insights, neuroimaging, neurobiological, and autism spectrum disorder. Results: The intricate relationship between the cerebellum and other brain regions linked to ASD has been highlighted by neurobiological research, which has shown abnormalities in neurotransmitter systems and cerebellar circuitry. The relevance of the cerebellum in the pathophysiology of ASD has been further highlighted by anatomical studies that have revealed evidence of cerebellar abnormalities, including changes in volume, morphology, and connectivity. Conclusion: Thorough knowledge of the cerebellum's function in ASD may lead to new understandings of the underlying mechanisms of the condition and make it easier to create interventions and treatments that are more specifically targeted at treating cerebellar dysfunction in ASD patients.

Imbalanced optimal feedback motor control system in spinocerebellar ataxia type 3.

BACKGROUND AND PURPOSE: Human motor planning and control depend highly on optimal feedback control systems, such as the neocortex-cerebellum circuit. Here, diffusion tensor imaging was used to verify the disruption of the neocortex-cerebellum circuit in spinocerebellar ataxia type 3 (SCA3), and the circuit's disruption correlation with SCA3 motor dysfunction was investigated. METHODS: This study included 45 patients with familial SCA3, aged 17-67 years, and 49 age- and sex-matched healthy controls, aged 21-64 years. Tract-based spatial statistics and probabilistic tractography was conducted using magnetic resonance images of the patients and controls. The correlation between the local probability of probabilistic tractography traced from the cerebellum and clinical symptoms measured using specified symptom scales was also calculated. RESULTS: The cerebellum-originated probabilistic tractography analysis showed that structural connectivity, mainly in the subcortical cerebellar-thalamo-cortical tract, was significantly reduced and the cortico-ponto-cerebellar tract was significantly stronger in the SCA3 group than in the control group. The enhanced tract was extended to the right lateral parietal region and the right primary motor cortex. The enhanced neocortex-cerebellum connections were highly associated with disease progression, including duration and symptomatic deterioration. Tractography probabilities from the cerebellar to parietal and sensorimotor areas were significantly negatively correlated with motor abilities in patients with SCA3. CONCLUSION: To our knowledge, this study is the first to reveal that disrupting the neocortex-cerebellum loop can cause SCA3-induced motor dysfunctions. The specific interaction between the cerebellar-thalamo-cortical and cortico-ponto-cerebellar pathways in patients with SCA3 and its relationship with ataxia symptoms provides a new direction for future research.

Isolated cerebellar stroke in a paediatric patient with typical haemolytic uraemic syndrome: a case report and literature review.

Haemolytic Uraemic Syndrome (HUS) is a rare medical condition characterised by microangiopathic haemolytic anaemia, thrombocytopenia, and acute kidney injury. Neurological complications are documented but rarely involve the cerebellum. We present a unique case of a 23-month-old male with HUS triggered by Escherichia coli-O157 (E.coli-O157) infection leading to an isolated cerebellar stroke.The patient initially presented with fever, bloody stools, and seizures. Confirmation of E.coli-O157 infection was obtained, and MRI revealed an isolated cerebellar stroke. Treatment included supportive care, anticoagulation for a right atrial thrombus, with gradual improvement observed.This case highlights the unusual occurrence of isolated cerebellar stroke in HUS patients, emphasising the importance of promptly recognizing manifestations of the central nervous system and the necessity for a multidisciplinary approach. Finally, a comprehensive literature review was conducted to identify cases of HUS patients with cerebellar involvement.

Surgical infarct volume reduction and functional outcomes in patients with ischemic cerebellar stroke: results from a multicentric retrospective study.

OBJECTIVE: Recent work on ischemic cerebellar stroke has suggested that the resection of infarcted tissue may lead to improved functional outcomes compared with decompressive surgery alone. Nonetheless, no studies have assessed the extent to which necrotic tissue should be resected or if there are any volumetric thresholds capable of predicting functional outcomes in this patient population. In this study, the authors aimed to determine potential thresholds for volume reduction in ischemic cerebellar stroke in an effort to optimize the management of ischemic cerebellar stroke and, in so doing, improve functional outcomes. METHODS: This study is a multicentric retrospective study of patients who underwent surgery for the management of ischemic cerebellar stroke. Volumetric analyses of infarcted tissue present on CT scans were performed before and after surgical intervention(s). The final infarct volume (FIV) was computed as a percentage of the initial infarct volume (postoperative infarct volume/preoperative infarct volume × 100). The primary endpoint was functional outcome at 3 months, as determined by the modified Rankin Scale (mRS) score; mRS scores 0-2 were considered as favorable and mRS scores 3-6 as unfavorable. Receiver operating characteristic curves were used to explore the relationship between postoperative infarct volumes and FIV versus mRS score, and Youden's index was used to estimate potential volumetric thresholds. RESULTS: A total of 91 patients were included in the study. The mean pre- and postoperative infarct volumes were 45.25 (SD 18.32) cm3 and 29.56 (SD 26.61) cm3, respectively. Patients undergoing necrosectomy, regardless of whether via craniotomy or craniectomy, were more likely to have a favorable outcome at discharge (OR 16.62, 95% CI 2.12-130.33; p = 0.008) and at 3 months (OR 24.12, 95% CI 3.03-192.18; p = 0.003) postoperatively. Postoperative infarct volumes ≤ 17 cm3 yielded a sensitivity of 77% and a specificity of 68% with regard to the prediction of favorable outcome at 3 months. The resection ≥ 50% of infarcted tissue was also predictive of favorable outcomes at 3 months (OR 7.7, 95% CI 2.7-21.8; p < 0.001). CONCLUSIONS: The reduction of necrotic tissue volumes by at least 50% and/or the reduction of the infarct volume by ≤ 17 cm3 appear to be associated with favorable outcomes in patients with surgically managed ischemic cerebellar strokes.

Coupling motor evoked potentials and BRAIN [18F]FDG-pet in amyotrophic lateral sclerosis: Preliminary findings on disease severity.

BACKGROUND: The diagnosis of amyotrophic lateral sclerosis (ALS) is primarily clinical, supported by the electromyographic examination to reveal signs of lower motor neuron damage. Identifying reliable markers of upper motor neuron (UMN) involvement is challenging. On this regard, the role of transcranial magnetic stimulation-induced motor-evoked potentials (TMS-MEPs), and its relationship with UMN burden, is still under investigation. OBJECTIVE: To evaluate the ability of TMS-MEPs in delineating the neurophysiological UMN damage, and to determine the relationship between TMS-MEPs and [18F]FDG-PET measures of neural dysfunction. METHODS: We retrospectively selected 13 ALS patients who underwent, during the diagnostic process, the TMS-MEPs and [18F]FDG-PET scans. Demographic and clinical data were collected. For the MEP evaluation, we considered normal MEP, absent MEP, or significantly increased central-motor-conduction-time. For [18F]FDG-PET, we conducted voxel-wise analyses, both at single-subject and group levels, exploring hypometabolism and hypermetabolism patterns in comparison with a large dataset of healthy controls (HC). RESULTS: Based on TMS-MEPs, we identified 4/13 patients with normal MEP in all limbs (GROUP-NO), while 9/13 had an abnormal MEP in at least one limb (GROUP-AB). Despite the [18F]FDG-PET single-subject analysis revealed heterogenous expression of regional hypo- and hyper-metabolism patterns in the patients, the group-level analysis revealed a common hypometabolism, involving the precentral gyrus and the supplementary motor area, the paracentral lobule and the anterior cingulate cortex in the GROUP-AB. Moreover, exclusively for the GROUP-AB compared with HC, a relative hypermetabolism was observed in the right cerebellum, right inferior and middle temporal gyrus. The GROUP-NO showed no specific cluster of hypo- and hyper-metabolism compared to HC. CONCLUSION: This study showed altered brain metabolism only in the ALS group with abnormal MEPs, suggesting an association between the two biomarkers in defining the UMN damage.

Neuroinflammation and Lysosomal Abnormalities Characterise the Essential Role for Oxidation Resistance 1 in the Developing and Adult Cerebellum.

Loss-of-function mutations in the TLDc family of proteins cause a range of severe childhood-onset neurological disorders with common clinical features that include cerebellar neurodegeneration, ataxia and epilepsy. Of these proteins, oxidation resistance 1 (OXR1) has been implicated in multiple cellular pathways related to antioxidant function, transcriptional regulation and cellular survival; yet how this relates to the specific neuropathological features in disease remains unclear. Here, we investigate a range of loss-of-function mouse model systems and reveal that constitutive deletion of Oxr1 leads to a rapid and striking neuroinflammatory response prior to neurodegeneration that is associated with lysosomal pathology. We go on to show that neuroinflammation and cell death in Oxr1 knockouts can be completely rescued by the neuronal expression of Oxr1, suggesting that the phenotype is driven by the cell-intrinsic defects of neuronal cells lacking the gene. Next, we generate a ubiquitous, adult inducible knockout of Oxr1 that surprisingly displays rapid-onset ataxia and cerebellar neurodegeneration, establishing for the first time that the distinctive pathology associated with the loss of Oxr1 occurs irrespective of developmental stage. Finally, we describe two new homozygous human pathogenic variants in OXR1 that cause neurodevelopmental delay, including a novel stop-gain mutation. We also compare functionally two missense human pathogenic mutations in OXR1, including one newly described here, that cause different clinical phenotypes but demonstrate partially retained neuroprotective activity against oxidative stress. Together, these data highlight the essential role of Oxr1 in modulating neuroinflammatory and lysosomal pathways in the mammalian brain and support the hypothesis that OXR1 protein dosage may be critical for pathological outcomes in disease.

Identification and Organization of a Postural Anti-Gravity Module in the Cerebellar Vermis.

The cerebellum is known to control the proper balance of isometric muscular contractions that maintain body posture. Current optogenetic manipulations of the cerebellar cortex output, however, have focused on ballistic body movements, examining movement initiation or perturbations. Here, by optogenetic stimulations of cerebellar Purkinje cells, which are the output of the cerebellar cortex, we evaluate body posture maintenance. By sequential analysis of body movement, we dissect the effect of optogenetic stimulation into a directly induced movement that is then followed by a compensatory reflex to regain body posture. We identify a module in the medial part of the anterior vermis which, through multiple muscle tone regulation, is involved in postural anti-gravity maintenance of the body. Moreover, we report an antero-posterior and medio-lateral functional segregation over the vermal lobules IV/V/VI. Taken together our results open new avenues for better understanding of the modular functional organization of the cerebellar cortex and its role in postural anti-gravity maintenance.

Understanding Cerebellar Input Stage through Computational and Plasticity Rules.

A central hypothesis concerning brain functioning is that plasticity regulates the signal transfer function by modifying the efficacy of synaptic transmission. In the cerebellum, the granular layer has been shown to control the gain of signals transmitted through the mossy fiber pathway. Until now, the impact of plasticity on incoming activity patterns has been analyzed by combining electrophysiological recordings in acute cerebellar slices and computational modeling, unraveling a broad spectrum of different forms of synaptic plasticity in the granular layer, often accompanied by forms of intrinsic excitability changes. Here, we attempt to provide a brief overview of the most prominent forms of plasticity at the excitatory synapses formed by mossy fibers onto primary neuronal components (granule cells, Golgi cells and unipolar brush cells) in the granular layer. Specifically, we highlight the current understanding of the mechanisms and their functional implications for synaptic and intrinsic plasticity, providing valuable insights into how inputs are processed and reconfigured at the cerebellar input stage.

Feasibility of a randomized, sham-controlled pilot study for accelerated rTMS-treatment of the cerebellum plus physiotherapy in CANVAS patients.

BACKGROUND: Cerebellar ataxia, neuropathy and bilateral vestibular areflexia (CANVAS) is a rare neurodegenerative disease affecting the cerebellum, the peripheral nervous system and the vestibular system. Due to the lack of approved drugs, therapy comprises physiotherapy and speech therapy. Transcranial magnetic stimulation is a promising non-invasive therapeutic option to complement classical symptomatic therapies. OBJECTIVE: To test feasibility of the combination of transcranial magnetic stimulation using an accelerated protocol and standard symptomatic therapy in patients with CANVAS. METHODS: Eight patients with genetically confirmed CANVAS were assigned to either verum or sham cerebellar transcranial magnetic stimulation using an accelerated protocol. Treatment duration was limited to 5 days. Additionally, patients in both groups received symptomatic therapy (speech and physiotherapy) for the duration of the study. RESULTS: All patients completed the stimulation protocol. Adverse events were rare. Ataxia severity improved in the verum group only. CONCLUSION: The combination of transcranial magnetic stimulation and classic symptomatic therapy is feasible in a neuro-rehabilitation setting and potentially ameliorates ataxia severity.

Cerebellar gray matter and white matter damage among older adults with prediabetes.

AIMS: To investigate alterations in cerebrum and cerebellum in prediabetes. Cerebellar injury in diabetes is traceable, but it has not been systematically studied, and whether cerebellar injury occurs and the degree of damage in prediabetes are not known. METHODS: The current study investigated cerebral and cerebellar gray matter volume, white matter volume, white matter microstructure and white matter hyperintensity on T1-weighted, T2-weighted fluid-attenuated inversion recovery and diffusion tensor imaging scans in 78 individuals with normal glucose metabolism, 92 with prediabetes, and 108 with type 2 diabetes. RESULTS: Participants with prediabetes showed significant gray matter and white matter atrophy, microstructural damage in the cerebellar and cerebral regions. Additionally, widespread structural alterations were observed in the diabetic stage. The function of the damaged brain area was further decoded in Neurosynth, and the damaged cerebellar area with prediabetic lesions was closely related to motor function, while the area affected by diabetes was related to complex cognitive function in addition to motor function. CONCLUSIONS: Cerebellar injury had already appeared in the prediabetic stage, and cerebellar injury was aggravated in the diabetic stage; therefore, the cerebellum is a key area that is damaged early in the development of diabetes.

A cerebellar granule cell-climbing fiber computation to learn to track long time intervals.

In classical cerebellar learning, Purkinje cells (PkCs) associate climbing fiber (CF) error signals with predictive granule cells (GrCs) that were active just prior (∼150 ms). The cerebellum also contributes to behaviors characterized by longer timescales. To investigate how GrC-CF-PkC circuits might learn seconds-long predictions, we imaged simultaneous GrC-CF activity over days of forelimb operant conditioning for delayed water reward. As mice learned reward timing, numerous GrCs developed anticipatory activity ramping at different rates until reward delivery, followed by widespread time-locked CF spiking. Relearning longer delays further lengthened GrC activations. We computed CF-dependent GrC→PkC plasticity rules, demonstrating that reward-evoked CF spikes sufficed to grade many GrC synapses by anticipatory timing. We predicted and confirmed that PkCs could thereby continuously ramp across seconds-long intervals from movement to reward. Learning thus leads to new GrC temporal bases linking predictors to remote CF reward signals-a strategy well suited for learning to track the long intervals common in cognitive domains.