Showing papers in "The Cerebellum in 2021"

Contribution of the Cerebellum and the Basal Ganglia to Language Production: Speech, Word Fluency, and Sentence Construction-Evidence from Pathology.

Abstract: Evidence reported in recent decades increasingly confirms that both the cerebellum and the basal ganglia, which are primarily involved in movement control, also have a significant role in a vast range of cognitive and affective functions. Evidence from pathology indicates that the disorders of some aspects of language production which follow damage of the cerebellum or respectively basal ganglia, i.e., disorders of speech, word fluency, and sentence construction, have identifiable neuropsychological profiles and that most manifestations can be specifically attributed to the dysfunctions of mechanisms supported by one or the other of these structures. The cerebellum and the basal ganglia are reciprocally interconnected. Thus, it is plausible that some disorders observed when damage involves one of these structures could be remote effects of abnormal activity in the other. However, in a purely clinical-neuropsychological perspective, primary and remote effects in the network are difficult to disentangle. Functional neuroimaging and non-invasive brain stimulation techniques likely represent the indispensable support for achieving this goal.

Decomposition of Reaching Movements Enables Detection and Measurement of Ataxia

Abstract: Technologies that enable frequent, objective, and precise measurement of ataxia severity would benefit clinical trials by lowering participation barriers and improving the ability to measure disease state and change. We hypothesized that analyzing characteristics of sub-second movement profiles obtained during a reaching task would be useful for objectively quantifying motor characteristics of ataxia. Participants with ataxia (N=88), participants with parkinsonism (N=44), and healthy controls (N=34) performed a computer tablet version of the finger-to-nose test while wearing inertial sensors on their wrists. Data features designed to capture signs of ataxia were extracted from participants’ decomposed wrist velocity time-series. A machine learning regression model was trained to estimate overall ataxia severity, as measured by the Brief Ataxia Rating Scale (BARS). Classification models were trained to distinguish between ataxia participants and controls and between ataxia and parkinsonism phenotypes. Movement decomposition revealed expected and novel characteristics of the ataxia phenotype. The distance, speed, duration, morphology, and temporal relationships of decomposed movements exhibited strong relationships with disease severity. The regression model estimated BARS with a root mean square error of 3.6 points, r2 = 0.69, and moderate-to-excellent reliability. Classification models distinguished between ataxia participants and controls and ataxia and parkinsonism phenotypes with areas under the receiver-operating curve of 0.96 and 0.89, respectively. Movement decomposition captures core features of ataxia and may be useful for objective, precise, and frequent assessment of ataxia in home and clinic environments.

Consensus on Virtual Management of Vestibular Disorders: Urgent Versus Expedited Care.

Abstract: The virtual practice has made major advances in the way that we care for patients in the modern era. The culture of virtual practice, consulting, and telemedicine, which had started several years ago, took an accelerated leap as humankind was challenged by the novel coronavirus pandemic (COVID19). The social distancing measures and lockdowns imposed in many countries left medical care providers with limited options in evaluating ambulatory patients, pushing the rapid transition to assessments via virtual platforms. In this novel arena of medical practice, which may form new norms beyond the current pandemic crisis, we found it critical to define guidelines on the recommended practice in neurotology, including remote methods in examining the vestibular and eye movement function. The proposed remote examination methods aim to reliably diagnose acute and subacute diseases of the inner-ear, brainstem, and the cerebellum. A key aim was to triage patients into those requiring urgent emergency room assessment versus non-urgent but expedited outpatient management. Physicians who had expertise in managing patients with vestibular disorders were invited to participate in the taskforce. The focus was on two topics: (1) an adequate eye movement and vestibular examination strategy using virtual platforms and (2) a decision pathway providing guidance about which patient should seek urgent medical care and which patient should have non-urgent but expedited outpatient management.

Mini-review: The Role of the Cerebellum in Visuomotor Adaptation.

Abstract: The incredible capability of the brain to quickly alter performance in response to ever-changing environment is rooted in the process of adaptation. The core aspect of adaptation is to fit an existing motor program to altered conditions. Adaptation to a visuomotor rotation or an external force has been well established as tools to study the mechanisms underlying sensorimotor adaptation. In this mini-review, we summarize recent findings from the field of visuomotor adaptation. We focus on the idea that the cerebellum plays a central role in the process of visuomotor adaptation and that interactions with cortical structures, in particular, the premotor cortex and the parietal cortex, may be crucial for this process. To this end, we cover a range of methodologies used in the literature that link cerebellar functions and visuomotor adaptation; behavioral studies in cerebellar lesion patients, neuroimaging and non-invasive stimulation approaches. The mini-review is organized as follows: first, we provide evidence that sensory prediction errors (SPE) in visuomotor adaptation rely on the cerebellum based on behavioral studies in cerebellar patients. Second, we summarize structural and functional imaging studies that provide insight into spatial localization as well as visuomotor adaptation dynamics in the cerebellum. Third, we discuss premotor - cerebellar interactions and how these may underlie visuomotor adaptation. And finally, we provide evidence from transcranial direct current and magnetic stimulation studies that link cerebellar activity, beyond correlational relationships, to visuomotor adaptation .

Feasibility of combining functional near-infrared spectroscopy with electroencephalography to identify chronic stroke responders to cerebellar transcranial direct current stimulation—a computational modeling and portable neuroimaging methodological study

Abstract: Feasibility of portable neuroimaging of cerebellar transcranial direct current stimulation (ctDCS) effects on the cerebral cortex has not been investigated vis-a-vis cerebellar lobular electric field strength. We studied functional near-infrared spectroscopy (fNIRS) in conjunction with electroencephalography (EEG) to measure changes in the brain activation at the prefrontal cortex (PFC) and the sensorimotor cortex (SMC) following ctDCS as well as virtual reality-based balance training (VBaT) before and after ctDCS treatment in 12 hemiparetic chronic stroke survivors. We performed general linear modeling (GLM) that putatively associated the lobular electric field strength with the changes in the fNIRS-EEG measures at the ipsilesional and contra-lesional PFC and SMC. Here, fNIRS-EEG measures were found in the latent space from canonical correlation analysis (CCA) between the changes in total hemoglobin (tHb) concentrations (0.01-0.07Hz and 0.07-0.13Hz bands) and log10-transformed EEG bandpower within 1-45 Hz where significant (Wilks' lambda>0.95) canonical correlations were found only for the 0.07-0.13-Hz band. Also, the first principal component (97.5% variance accounted for) of the mean lobular electric field strength was a good predictor of the latent variables of oxy-hemoglobin (O2Hb) concentrations and log10-transformed EEG bandpower. GLM also provided insights into non-responders to ctDCS who also performed poorly in the VBaT due to ideomotor apraxia. Future studies should investigate fNIRS-EEG joint-imaging in a larger cohort to identify non-responders based on GLM fitting to the fNIRS-EEG data.

The Effects of Midline Cerebellar rTMS on Human Pharyngeal Cortical Activity in the Intact Swallowing Motor System

Abstract: We sought to compare the effects of 10 Hz cerebellar vermis (vs. unilateral hemispheric and sham) repetitive transcranial magnetic stimulation (rTMS) on cortical neuroelectrical activity and thereafter 10 Hz cerebellar vermis (vs. sham) rTMS on swallowing behaviour. Healthy participants (n = 25) were randomly allocated to receive vermis, unilateral hemisphere or sham 10 Hz cerebellar rTMS. Recordings were made using pharyngeal electromyography and manometry catheters, obtaining motor-evoked potentials (MEPs) and pressure recordings. The amplitudes of MEPs elicited using single-pulse TMS delivered to the pharyngeal areas of the motor cortex bilaterally were measured pre- and post-cerebellar stimulation. As in previous studies, abductor policis brevis (APB) MEPs were measured to assess post-rTMS modulation specificity. Swallowing was assessed using a swallowing accuracy task. Measurements were made at baseline and 15-min intervals for an hour post-intervention. Measurements involved TMS being used to elicit 10 MEPs bilaterally over the pharyngeal areas of the motor cortex, over the APB cortical representation adjacent to the pharyngeal area with the lowest resting motor threshold and 5 MEPs bilaterally over pharyngeal areas of the cerebellar hemispheres. Swallowing accuracy was assessed by giving participants 10 attempts to swallow and hit a digital target. Cerebellar vermis rTMS caused significant suppression of cortical pharyngeal MEP amplitudes compared with unilateral rTMS and sham (P = 0.0005, 0.002). APB and cerebellar MEP amplitudes were unaffected as were pharyngeal and APB MEP latencies. Following cerebellar vermis rTMS there was a significant reduction in swallowing accuracy compared with sham (P = 0.001). Our findings demonstrate cerebellar vermis rTMS exerts a suppressive effect on pharyngeal motor cortical activity and swallowing behaviour.

The Efficacy and Safety of Transcranial Direct Current Stimulation for Cerebellar Ataxia: a Systematic Review and Meta-Analysis.

Abstract: A promising new approach, transcranial direct current stimulation (tDCS) has recently been used as a therapeutic modality for cerebellar ataxia. However, the strength of the conclusions drawn from individual studies in the current literature may be constrained by the small sample size of each trial. Following a systematic literature retrieval of studies, meta-analyses were conducted by pooling the standardized mean differences (SMDs) using random-effects models to assess the efficacy of tDCS on cerebellar ataxia, measured by standard clinical rating scales. Domain-specific effects of tDCS on gait and hand function were further evaluated based on 8-m walk and 9-hole peg test performance times, respectively. To determine the safety of tDCS, the incidences of adverse effects were analyzed using risk differences. Out of 293 citations, 5 randomized controlled trials involving a total of 72 participants with cerebellar ataxia were included. Meta-analysis indicated a 26.1% (p = 0.003) improvement in ataxia immediately after tDCS with sustained efficacy over months (28.2% improvement after 3 months, p = 0.04) when compared with sham stimulation. tDCS seems to be domain-specific as the current analysis suggested a positive effect on gait (16.3% improvement, p = 0.04) and failed to reveal differences for hand function (p = 0.10) with respect to sham. The incidence of adverse events in tDCS and sham groups was similar. tDCS is an effective intervention for mitigating ataxia symptoms with lasting results that can be sustained for months. This treatment shows preferential effects on gait ataxia and is relatively safe.

Free-Living Motor Activity Monitoring in Ataxia-Telangiectasia

Abstract: With disease-modifying approaches under evaluation in ataxia-telangiectasia and other ataxias, there is a need for objective and reliable biomarkers of free-living motor function. In this study, we test the hypothesis that metrics derived from a single wrist sensor worn at home provide accurate, reliable, and interpretable information about neurological disease severity in children with A-T. A total of 15 children with A-T and 15 age- and sex-matched controls wore a sensor with a triaxial accelerometer on their dominant wrist for 1 week at home. Activity intensity measures, derived from the sensor data, were compared with in-person neurological evaluation on the Brief Ataxia Rating Scale (BARS) and performance on a validated computer mouse task. Children with A-T were inactive the same proportion of each day as controls but produced more low intensity movements (p < 0.01; Cohen’s d = 1.48) and fewer high intensity movements (p < 0.001; Cohen’s d = 1.71). The range of activity intensities was markedly reduced in A-T compared to controls (p < 0.0001; Cohen’s d = 2.72). The activity metrics correlated strongly with arm, gait, and total clinical severity (r: 0.71–0.87; p < 0.0001), correlated with specific computer task motor features (r: 0.67–0.92; p < 0.01), demonstrated high reliability (r: 0.86–0.93; p < 0.00001), and were not significantly influenced by age in the healthy control group. Motor activity metrics from a single, inexpensive wrist sensor during free-living behavior provide accurate and reliable information about diagnosis, neurological disease severity, and motor performance. These low-burden measurements are applicable independent of ambulatory status and are potential digital behavioral biomarkers in A-T.

Update on Cerebellar Ataxia with Neuropathy and Bilateral Vestibular Areflexia Syndrome (CANVAS)

Abstract: The syndrome of cerebellar ataxia with neuropathy and bilateral vestibular areflexia (CANVAS) has emerged progressively during the last 30 years. It was first outlined by the neurootology/neurophysiology community in the vestibular areflexic patients, through the description of patients slowly developing late-onset cerebellar ataxia and bilateral vestibulopathy. The characteristic deficit of visuo-vestibulo-ocular reflex (VVOR) due to the impaired slow stabilizing eye movements was put forward and a specific disease subtending this syndrome was suggested. The association to a peripheral sensory axonal neuropathy was described later on, with neuropathological studies demonstrating that both sensory neuropathy and vestibular areflexia were diffuse ganglionopathy. Clinical and electrophysiological criteria of CANVAS were then proposed in 2016. Besides the classical triad, frequent chronic cough, signs of dysautonomia and neurogenic pains were frequently observed. From the beginning of published cohorts, sporadic as well as familial cases were reported, the last suggestive of an autosomal recessive mode of transmission. The genetic disorder was discovered in 2019, under the form of abnormal biallelic expansion in the replication factor C subunit 1 (RFC1) in a population of late-onset ataxia. This pathological expansion was found in 100% of the familial form and 92% of sporadic ones when the triad was complete. But using the genetic criteria, the phenotype of CANVAS seems to expand, for exemple including patients with isolated neuronopathy. We propose here to review the clinical, electrophysiological, anatomical, genetic aspect of CANVAS in light of the recent discovery of the genetic aetiology, and discuss differential diagnosis, neuropathology and physiopathology.

Increased Purkinje Cell Complex Spike and Deep Cerebellar Nucleus Synchrony as a Potential Basis for Syndromic Essential Tremor. A Review and Synthesis of the Literature

Abstract: We review advances in understanding Purkinje cell (PC) complex spike (CS) physiology that suggest increased CS synchrony underlies syndromic essential tremor (ET). We searched PubMed for papers describing factors that affect CS synchrony or cerebellar circuits potentially related to tremor. Inferior olivary (IO) neurons are electrically coupled, with the degree of coupling controlled by excitatory and GABAergic inputs. Clusters of coupled IO neurons synchronize CSs within parasagittal bands via climbing fibers (Cfs). When motor cortex is stimulated in rats at varying frequencies, whisker movement occurs at ~10 Hz, correlated with synchronous CSs, indicating that the IO/CS oscillatory rhythm gates movement frequency. Intra-IO injection of the GABAA receptor antagonist picrotoxin increases CS synchrony, increases whisker movement amplitude, and induces tremor. Harmaline and 5-HT2a receptor activation also increase IO coupling and CS synchrony and induce tremor. The hotfoot17 mouse displays features found in ET brains, including cerebellar GluRδ2 deficiency and abnormal PC Cf innervation, with IO- and PC-dependent cerebellar oscillations and tremor likely due to enhanced CS synchrony. Heightened coupling within the IO oscillator leads, through its dynamic control of CS synchrony, to increased movement amplitude and, when sufficiently intense, action tremor. Increased CS synchrony secondary to aberrant Cf innervation of multiple PCs likely also underlies hotfoot17 tremor. Deep cerebellar nucleus (DCN) hypersynchrony may occur secondary to increased CS synchrony but might also occur from PC axonal terminal sprouting during partial PC loss. Through these combined mechanisms, increased CS/DCN synchrony may plausibly underlie syndromic ET.

Consensus Paper: Novel Directions and Next Steps of Non-invasive Brain Stimulation of the Cerebellum in Health and Disease.

Abstract: The cerebellum is involved in multiple closed-loops circuitry which connect the cerebellar modules with the motor cortex, prefrontal, temporal, and parietal cortical areas, and contribute to motor control, cognitive processes, emotional processing, and behavior. Among them, the cerebello-thalamo-cortical pathway represents the anatomical substratum of cerebellum-motor cortex inhibition (CBI). However, the cerebellum is also connected with basal ganglia by disynaptic pathways, and cerebellar involvement in disorders commonly associated with basal ganglia dysfunction (e.g., Parkinson’s disease and dystonia) has been suggested. Lately, cerebellar activity has been targeted by non-invasive brain stimulation (NIBS) techniques including transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) to indirectly affect and tune dysfunctional circuitry in the brain. Although the results are promising, several questions remain still unsolved. Here, a panel of experts from different specialties (neurophysiology, neurology, neurosurgery, neuropsychology) reviews the current results on cerebellar NIBS with the aim to derive the future steps and directions needed. We discuss the effects of TMS in the field of cerebellar neurophysiology, the potentials of cerebellar tDCS, the role of animal models in cerebellar NIBS applications, and the possible application of cerebellar NIBS in motor learning, stroke recovery, speech and language functions, neuropsychiatric and movement disorders.

Functional Alterations in Cerebellar Functional Connectivity in Anxiety Disorders

Abstract: Adolescents with anxiety disorders exhibit excessive emotional and somatic arousal. Neuroimaging studies have shown abnormal cerebral cortical activation and connectivity in this patient population. The specific role of cerebellar output circuitry, specifically the dentate nuclei (DN), in adolescent anxiety disorders remains largely unexplored. Resting-state functional connectivity analyses have parcellated the DN, the major output nuclei of the cerebellum, into three functional territories (FTs) that include default-mode, salience-motor, and visual networks. The objective of this study was to understand whether FTs of the DN are implicated in adolescent anxiety disorders. Forty-one adolescents (mean age 15.19 ± 0.82, 26 females) with one or more anxiety disorders and 55 age- and gender-matched healthy controls completed resting-state fMRI scans and a self-report survey on anxiety symptoms. Seed-to-voxel functional connectivity analyses were performed using the FTs from DN parcellation. Brain connectivity metrics were then correlated with State-Trait Anxiety Inventory (STAI) measures within each group. Adolescents with an anxiety disorder showed significant hyperconnectivity between salience-motor DN FT and cerebral cortical salience-motor regions compared to controls. Salience-motor FT connectivity with cerebral cortical sensorimotor regions was significantly correlated with STAI-trait scores in HC (R2 = 0.41). Here, we report DN functional connectivity differences in adolescents diagnosed with anxiety, as well as in HC with variable degrees of anxiety traits. These observations highlight the relevance of DN as a potential clinical and sub-clinical marker of anxiety.

Efficacy of Intensive Cerebellar Intermittent Theta Burst Stimulation (iCiTBS) in Treatment-Resistant Schizophrenia: a Randomized Placebo-Controlled Study.

Abstract: Trans-cranial magnetic stimulation (TMS) can noninvasively modulate specific brain regions to dissipate symptoms in treatment-resistant schizophrenia (TRS). Citing impaired resting state connectivity between cerebellum and prefrontal cortex in schizophrenia, we aimed to study the effect of intermittent theta burst stimulation (iTBS) targeting midline cerebellum in TRS subjects on a randomized rater blinded placebo control study design. In this study, 36 patients were randomly allocated (using block randomization method) to active and sham iTBS groups. They were scheduled to receive ten iTBS sessions, two per day (total of 1200 pulses) for 5 days in a week. The Positive and Negative Syndrome Scale (PANSS), Brief Psychiatric Rating Scale (BPRS), Schizophrenia Cognition Rating Scale (SCoRS), Simpson-Angus Extrapyramidal Side Effects Scale (SAS), and Clinical Global Impression (CGI) were assessed at baseline, after last session, and at 2 weeks post-rTMS. Thirty patients (16 and 14 in active and sham groups) completed the study. Intention to treat analysis (ITT) using mixed (growth curve) model analysis was conducted. No significant group (active vs sham) × time (pretreatment–end of 10th session–end of 2 weeks post iTBS) interaction was found for any of the variable. No major side effects were reported. Our study fails to show a significant effect of intensive cerebellar iTBS (iCiTBS) on schizophrenia psychopathology, cognitive functions, and global improvement, compared with sham stimulation, in treatment resistant cases. However, we conclude that it is safe and well tolerated. Trials using better localization technique with large sample, longer duration, and better dosing protocols are needed.

The Contribution of Neuroimaging to the Understanding of Essential Tremor Pathophysiology: a Systematic Review.

Abstract: Essential tremor (ET) is one of the most common movement disorders. Over the last 10 years, magnetic resonance imaging (MRI) has shed light on the structural and functional abnormalities possibly involved in ET pathophysiology. In this systematic review, we aimed to identify the cortical and subcortical structures involved and the role that different brain areas play in the pathophysiology of motor and non-motor ET features. We found that structural (grey and white matter) cerebellar damage and connectivity alterations between the cerebellum and various cortical areas play a role in both motor and non-motor symptoms of ET. In particular, many studies found an association between MRI findings and non-motor symptoms.

New Horizons on Non-invasive Brain Stimulation of the Social and Affective Cerebellum.

Abstract: The cerebellum is increasingly attracting scientists interested in basic and clinical research of neuromodulation. Here, we review available studies that used either transcranial magnetic stimulation (TMS) or transcranial direct current stimulation (tDCS) to examine the role of the posterior cerebellum in different aspects of social and affective cognition, from mood regulation to emotion discrimination, and from the ability to identify biological motion to higher-level social inferences (mentalizing). We discuss how at the functional level the role of the posterior cerebellum in these different processes may be explained by a generic prediction mechanism and how the posterior cerebellum may exert this function within different cortico-cerebellar and cerebellar limbic networks involved in social cognition. Furthermore, we suggest to deepen our understanding of the cerebro-cerebellar circuits involved in different aspects of social cognition by employing promising stimulation approaches that have so far been primarily used to study cortical functions and networks, such as paired-pulse TMS, frequency-tuned stimulation, state-dependent protocols, and chronometric TMS. The ability to modulate cerebro-cerebellar connectivity opens up possible clinical applications for improving impairments in social and affective skills associated with cerebellar abnormalities.

Antisense Oligonucleotide Therapy Targeted Against ATXN3 Improves Potassium Channel-Mediated Purkinje Neuron Dysfunction in Spinocerebellar Ataxia Type 3.

Abstract: Spinocerebellar ataxia type 3 (SCA3) is the second-most common CAG repeat disease, caused by a glutamine-encoding expansion in the ATXN3 protein. SCA3 is characterized by spinocerebellar degeneration leading to progressive motor incoordination and early death. Previous studies suggest that potassium channel dysfunction underlies early abnormalities in cerebellar cortical Purkinje neuron firing in SCA3. However, cerebellar cortical degeneration is often modest both in the human disease and mouse models of SCA3, raising uncertainty about the role of cerebellar dysfunction in SCA3. Here, we address this question by investigating Purkinje neuron excitability in SCA3. In early-stage SCA3 mice, we confirm a previously identified increase in excitability of cerebellar Purkinje neurons and associate this excitability with reduced transcripts of two voltage-gated potassium (KV) channels, Kcna6 and Kcnc3, as well as motor impairment. Intracerebroventricular delivery of antisense oligonucleotides (ASO) to reduce mutant ATXN3 restores normal excitability to SCA3 Purkinje neurons and rescues transcript levels of Kcna6 and Kcnc3. Interestingly, while an even broader range of KV channel transcripts shows reduced levels in late-stage SCA3 mice, cerebellar Purkinje neuron physiology was not further altered despite continued worsening of motor impairment. These results suggest the progressive motor phenotype observed in SCA3 may not reflect ongoing changes in the cerebellar cortex but instead dysfunction of other neuronal structures within and beyond the cerebellum. Nevertheless, the early rescue of both KV channel expression and neuronal excitability by ASO treatment suggests that cerebellar cortical dysfunction contributes meaningfully to motor dysfunction in SCA3.

Safety and Outcomes of Dentate Nucleus Deep Brain Stimulation for Cerebellar Ataxia.

Abstract: Cerebellar symptoms remain orphan of treatment options despite being prevalent and incapacitating. Investigate whether dentate nucleus deep brain stimulation (DN DBS) is safe and leads to improvements in cerebellar symptoms when compared to sham stimulation. This randomized double-blind crossover pilot trial enrolled five patients with spinocerebellar ataxia type 3 or post-lesion ataxia. Active or sham phases were randomly performed three months apart. The primary outcome was ataxia improvement as measured by the Scale for the Assessment and Rating of Ataxia (SARA) after the active compared to the sham period. Secondary outcome measures included safety and tolerability, the Fahn–Tolosa–Marin Tremor Rating Scale (FTMRS), quality of life measurements, and patients’ global impression of change. The effects on ataxia were numerically better in four out of five patients after active versus sham stimulation. The composite SARA score did not change after comparing active to sham stimulation (8.6 ± 3.6 versus 10.1 ± 4.1; p = 0.223). The FTMRS showed significant improvement after active stimulation versus sham (18.0 ± 17.2 versus 22.2 ± 19.5; p = 0.039) as did patients’ global impression of change (p = 0.038). The quality of life was not modified by stimulation (p = 0.337). DN DBS was well tolerated without serious adverse events. One patient had the electrode repositioned. DN DBS is a safe and well tolerated procedure that is effective in alleviating cerebellar tremor. In this small cohort of ataxic patients, DN DBS did not achieve statistical significance for ataxia improvement.

Post-symptomatic Delivery of Brain-Derived Neurotrophic Factor (BDNF) Ameliorates Spinocerebellar Ataxia Type 1 (SCA1) Pathogenesis.

Abstract: Spinocerebellar ataxia type 1 (SCA1) is a fatal neurodegenerative disease caused by an abnormal expansion of CAG repeats in the Ataxin1 (ATXN1) gene. SCA1 is characterized by motor deficits, cerebellar neurodegeneration, and gliosis and gene expression changes. Expression of brain-derived neurotrophic factor (BDNF), growth factor important for the survival and function of cerebellar neurons, is decreased in ATXN1[82Q] mice, the Purkinje neuron specific transgenic mouse model of SCA1. As this decrease in BDNF expression may contribute to cerebellar neurodegeneration, we tested whether delivery of extrinsic human BDNF via osmotic ALZET pumps has a beneficial effect on disease severity in this mouse model of SCA1. Additionally, to test the effects of BDNF on established and progressing cerebellar pathogenesis and motor deficits, we delivered BDNF post-symptomatically. We have found that post-symptomatic delivery of extrinsic BDNF ameliorated motor deficits and cerebellar pathology (i.e., dendritic atrophy of Purkinje cells, and astrogliosis) indicating therapeutic potential of BDNF even after the onset of symptoms in SCA1. However, BDNF did not alter Purkinje cell gene expression changes indicating that certain aspects of disease pathogenesis cannot be ameliorated/slowed down with BDNF and that combinational therapies may be needed.

Functional Convergence of Motor and Social Processes in Lobule IV/V of the Mouse Cerebellum.

Abstract: Topographic organization of the cerebellum is largely segregated into the anterior and posterior lobes that represent its "motor" and "non-motor" functions, respectively. Although patients with damage to the anterior cerebellum often exhibit motor deficits, it remains unclear whether and how such an injury affects cognitive and social behaviors. To address this, we perturbed the activity of major anterior lobule IV/V in mice by either neurotoxic lesion or chemogenetic excitation of Purkinje cells in the cerebellar cortex. We found that both of the manipulations impaired motor coordination, but not general locomotion or anxiety-related behavior. The lesioned animals showed memory deficits in object recognition and social-associative recognition tests, which were confounded by a lack of exploration. Chemogenetic excitation of Purkinje cells disrupted the animals' social approach in a less-preferred context and social memory, without affecting their overall exploration and object-based memory. In a free social interaction test, the two groups exhibited less interaction with a stranger conspecific. Subsequent c-Fos imaging indicated that decreased neuronal activities in the medial prefrontal cortex, hippocampal dentate gyrus, parahippocampal cortices, and basolateral amygdala, as well as disorganized modular structures of the brain networks might underlie the reduced social interaction. These findings suggest that the anterior cerebellum plays an intricate role in processing motor, cognitive, and social functions.

The Cerebellum and Implicit Sequencing: Evidence from Cerebellar Ataxia

Abstract: The cerebellum recognizes sequences from prior experiences and uses this information to generate internal models that predict future outcomes in a feedforward manner [Front Hum Neurosci 8: 475, 2014; Cortex 47: 137-44, 2011; Cerebellum 7: 611-5, 2008; J Neurosci 26: 9107-16, 2006]. This process has been well documented in the motor domain, but the cerebellum's role in cognitive sequencing, within the context of implicit versus explicit processes, is not well characterized. In this study, we tested individuals with cerebellar ataxia and healthy controls to clarify the role of the cerebellum sequencing using variations on implicit versus explicit and motor versus cognitive demands across five experiments. Converging results across these studies suggest that cerebellar feedforward mechanisms may be necessary for sequencing in the implicit domain only. In the ataxia group, rhythmic tapping, rate of motor learning, and implicit sequence learning were impaired. However, for cognitive sequencing that could be accomplished using explicit strategies, the cerebellar group performed normally, as though they shifted to extra-cerebellar mechanisms to compensate. For example, when cognitive and motor functions relied on cerebellar function simultaneously, the ataxia group's motor function was unaffected, in contrast to that of controls whose motor performance declined as a function of cognitive load. These findings indicated that the cerebellum is not critical for all forms of sequencing per se. Instead, it plays a fundamental role for sequencing within the implicit domain, whether functions are motor or cognitive. Moreover, individuals with cerebellar ataxia are generally able to compensate for cognitive sequencing when explicit strategies are available in order to preserve resources for motor function.

Clinical Characteristics and Management of 50 Patients with Anti-GAD Ataxia: Gluten-Free Diet Has a Major Impact.

Abstract: The objective of this study is to report the clinical characteristics and treatment of patients with progressive cerebellar ataxia associated with anti-GAD antibodies. We performed a retrospective review of all patients with anti-GAD ataxia managed at the Sheffield Ataxia Centre over the last 25 years. We identified 50 patients (62% females) with anti-GAD ataxia. The prevalence was 2.5% amongst 2000 patients with progressive ataxia of various causes. Mean age at onset was 55 and mean duration 8 years. Gaze-evoked nystagmus was present in 26%, cerebellar dysarthria in 26%, limb ataxia in 44% and gait ataxia in 100%. Nine patients (18%) had severe, 12 (24%) moderate and 29 (58%) mild ataxia. Ninety percent of patients had a history of additional autoimmune diseases. Family history of autoimmune diseases was seen in 52%. Baseline MR spectroscopy of the vermis was abnormal at presentation in 72%. Thirty-five patients (70%) had serological evidence of gluten sensitivity. All 35 went on gluten-free diet (GFD). Eighteen (51%) improved, 13 (37%) stabilised, 3 have started the GFD too recently to draw conclusions and one deteriorated. Mycophenolate was used in 16 patients, 7 (44%) improved, 2 stabilised, 6 have started the medication too recently to draw conclusions and one did not tolerate the drug. There is considerable overlap between anti-GAD ataxia and gluten ataxia. For those patients with both, strict GFD alone can be an effective treatment. Patients with anti-GAD ataxia and no gluten sensitivity respond well to immunosuppression.

The Involvement of the Posterior Cerebellum in Reconstructing and Predicting Social Action Sequences.

Abstract: Recent advances in social neuroscience have highlighted the critical role of the cerebellum and especially the posterior cerebellar Crus in social mentalizing (i.e., theory of mind). Research in the past 5 years has provided growing evidence supporting the view that the posterior cerebellum builds internal action models of our social interactions to predict how other people's actions will be executed, and what our most likely responses to these actions will be. This paper presents an overview of a series of fMRI experiments on novel tasks involving a combination of (a) the learning or generation of chronological sequences of social actions either in an explicit or implicit manner, which (b) require social mentalizing on another person's mental state such as goals, beliefs, and implied traits. Together, the results strongly confirm the central role of the posterior cerebellar Crus in identifying and automatizing action sequencing during social mentalizing, and in predicting future action sequences based on social mentalizing inferences about others. This research program has important implications: It provides for the first time (a) fruitful starting points for diagnosing and investigating social sequencing dysfunctions in a variety of mental disorders which have also been related to cerebellar dysfunctions, (b) provides the necessary tools for testing whether non-invasive neurostimulation targeting the posterior cerebellum has a causal effect on social functioning, and (c) whether these stimulation techniques and training programs guided by novel cerebellar social sequencing insights, can be exploited to increase posterior cerebellar plasticity in order to alleviate social impairments in mental disorders.

The Cerebellum in Drug-naive Children with Tourette Syndrome and Obsessive-Compulsive Disorder.

Abstract: Tourette syndrome (TS) and obsessive-compulsive disorder (OCD) are two neurodevelopmental disorders characterized by repetitive behaviors. Our recent study in drug-naive children with TS and OCD provided evidence of cerebellar involvement in both disorders. In addition, cerebellar functional connectivity (FC) was similar in TS patients without comorbidities (TSpure) and TS patients with OCD comorbidity (TS + OCD), but differed in pure OCD patients. To investigate in detail the cerebellar involvement in the pathophysiology of TS and OCD, we explored cerebellar structural and functional abnormalities in drug-naive children with TSpure, TS + OCD, and OCD and assessed possible correlations with severity scores. We examined 53 drug-naive children, classified as TSpure (n = 16), TS + OCD (n = 14), OCD (n = 11), or controls (n = 12). All subjects underwent a multimodal 3T magnetic resonance imaging examination. Cerebellar lobular volumes and quantitative diffusion tensor imaging parameters of cerebellar peduncles were used as measures of structural integrity. The dentate nucleus was selected as a region of interest to examine cerebello-cerebral functional connectivity alterations. Structural analysis revealed that both TSpure and TS + OCD patients had higher fractional anisotropy in cerebellar peduncles than controls. Conversely, OCD patients were characterized by lower fractional anisotropy than both controls and TSpure and TS + OCD patients. Lastly, cerebellar functional connectivity analysis revealed significant alterations in the cerebello-thalamo-cortical circuit in TSpure, TS + OCD, and OCD patients. Early cerebellar structural and functional changes in drug-naive pediatric TSpure, TS + OCD, and OCD patients support a primary role of the cerebellum in the pathophysiology of these disorders.

Consensus Paper: Strengths and Weaknesses of Animal Models of Spinocerebellar Ataxias and Their Clinical Implications

Abstract: Spinocerebellar ataxias (SCAs) represent a large group of hereditary degenerative diseases of the nervous system, in particular the cerebellum, and other systems that manifest with a variety of progressive motor, cognitive, and behavioral deficits with the leading symptom of cerebellar ataxia. SCAs often lead to severe impairments of the patient's functioning, quality of life, and life expectancy. For SCAs, there are no proven effective pharmacotherapies that improve the symptoms or substantially delay disease progress, i.e., disease-modifying therapies. To study SCA pathogenesis and potential therapies, animal models have been widely used and are an essential part of pre-clinical research. They mainly include mice, but also other vertebrates and invertebrates. Each animal model has its strengths and weaknesses arising from model animal species, type of genetic manipulation, and similarity to human diseases. The types of murine and non-murine models of SCAs, their contribution to the investigation of SCA pathogenesis, pathological phenotype, and therapeutic approaches including their advantages and disadvantages are reviewed in this paper. There is a consensus among the panel of experts that (1) animal models represent valuable tools to improve our understanding of SCAs and discover and assess novel therapies for this group of neurological disorders characterized by diverse mechanisms and differential degenerative progressions, (2) thorough phenotypic assessment of individual animal models is required for studies addressing therapeutic approaches, (3) comparative studies are needed to bring pre-clinical research closer to clinical trials, and (4) mouse models complement cellular and invertebrate models which remain limited in terms of clinical translation for complex neurological disorders such as SCAs.

A Causal Role of the Cerebellum in Auditory Feedback Control of Vocal Production

Abstract: Accumulating evidence demonstrates that the cerebellum is involved in a variety of cognitive functions. Recently, impaired auditory-motor integration for vocal control has been identified in patients with cerebellar degeneration, characterized by abnormally enhanced vocal compensations for pitch perturbations. However, the causal relationship between the cerebellum and auditory feedback during vocal production remains unclear. By applying anodal transcranial direct current stimulation (a-tDCS) over right cerebellum, the present study investigated cerebellar contributions to auditory-motor processing of feedback errors during vocal pitch regulation. Twenty young adults participated in a frequency-altered-feedback (FAF) task, in which they vocalized vowel sounds and heard their voice unexpectedly pitch-shifted by ± 50 or ± 200 cents. Active or sham cerebellar a-tDCS was applied either prior to or during the FAF task. Compensatory vocal responses to pitch perturbations were measured and compared across the conditions. Active cerebellar a-tDCS led to significantly larger and slower vocal compensations for pitch perturbations than sham stimulation. Moreover, this modulatory effect was observed regardless of the timing of cerebellar a-tDCS as well as the size and direction of the pitch perturbation. These findings provide the first causal evidence that the cerebellum is essentially involved in auditory feedback control of vocal production. Enhanced and slowed vocal compensations caused by cerebellar a-tDCS may be related to its inhibition on the prefrontal cortex that exerts inhibitory control over vocal compensation behavior, suggesting the importance of the cerebrocerebellar connections in this feedback control process.

Diagnostic Approach to Cerebellar Hypoplasia

Abstract: Cerebellar hypoplasia (CH) refers to a cerebellum of reduced volume with preserved shape. CH is associated with a broad heterogeneity in neuroradiologic features, etiologies, clinical characteristics, and neurodevelopmental outcomes, challenging physicians evaluating children with CH. Traditionally, neuroimaging has been a key tool to categorize CH based on the pattern of cerebellar involvement (e.g., hypoplasia of cerebellar vermis only vs. hypoplasia of both the vermis and cerebellar hemispheres) and the presence of associated brainstem and cerebral anomalies. With the advances in genetic technologies of the recent decade, many novel CH genes have been identified, and consequently, a constant updating of the literature and revision of the classification of cerebellar malformations are needed. Here, we review the current literature on CH. We propose a systematic approach to recognize specific neuroimaging patterns associated with CH, based on whether the CH is isolated or associated with posterior cerebrospinal fluid anomalies, specific brainstem or cerebellar malformations, brainstem hypoplasia with or without cortical migration anomalies, or dysplasia. The CH radiologic pattern and clinical assessment will allow the clinician to guide his investigations and genetic testing, give a more precise diagnosis, screen for associated comorbidities, and improve prognostication of associated neurodevelopmental outcomes.

The Role of the Posterior Cerebellum in Dysfunctional Social Sequencing

Abstract: Recent advances in social neuroscience have highlighted the critical role of the cerebellum in social cognition, and especially the posterior cerebellum. Studies have supported the view that the posterior cerebellum builds internal action models of our social interactions to predict how other people’s actions will be executed and what our most likely responses are to these actions. This mechanism allows to better anticipate action sequences during social interactions in an automatic and intuitive way and to fine-tune these anticipations, making it easier to understand other’s social behaviors and mental states (e.g., beliefs, intentions, traits). In this paper, we argue that the central role of the posterior cerebellum in identifying and automatizing social action sequencing provides a fruitful starting point for investigating social dysfunctions in a variety of clinical pathologies, such as autism, obsessive–compulsive and bipolar disorder, depression, and addiction. Our key hypothesis is that dysfunctions of the posterior cerebellum lead to under- or overuse of inflexible social routines and lack of plasticity for learning new, more adaptive, social automatisms. We briefly review past research supporting this view and propose a program of research to test our hypothesis. This approach might alleviate a variety of mental problems of individuals who suffer from inflexible automatizations that stand in the way of adjustable and intuitive social behavior, by increasing posterior cerebellar plasticity using noninvasive neurostimulation or neuro-guided training programs.

Treatment Response of Deferiprone in Infratentorial Superficial Siderosis: a Systematic Review.

Abstract: Superficial siderosis describes haemosiderin deposition on the surface of the brain. When present on infratentorial structures, it can cause ataxia, sensorineural hearing loss and pyramidal signs. There is no proven treatment and patients experience slow progression of symptoms. Iron-chelating agents have been suggested as a therapeutic option and deferiprone is suited as it crosses the blood-brain barrier. However, deferiprone is reported to have a 1–2% risk of agranulocytosis. We performed a systematic review on treatment of infratentorial superficial siderosis with deferiprone based on PRISMA guidelines. Studies were included if in English or an English language translation was available, were about human subjects and referred to patients with ataxia. Studies were excluded if they did not possess an English translation, included animal studies or did not have ataxia. Studies were excluded if they discussed cerebral amyloid angiopathy or siderosis of other regions. Eleven papers were included. We identified 69 patients. Seventeen patients (25%) discontinued the drug. The most encountered adverse effect was anaemia (21.7%). Neutropaenia was observed in 8.7% and agranulocytosis in 5.8% of patients. Clinically, response varied, and stability or improvement was seen across neurological domains in 6 studies while 5 showed a mixed response. On imaging, 13 (28.9%) patients improved, 24 (53.3%) stabilised and 8 (17.8%) deteriorated. A prospective international centralised register of patients should be developed to inform the design and conduct of a multicentre, placebo-controlled, randomised clinical trial to evaluate the efficacy of deferiprone. The evidence from this systematic review is that deferiprone is a promising intervention.

Association Between Greater Cerebellar Network Connectivity and Improved Phonemic Fluency Performance After Exercise Training in Older Adults

Abstract: Little is known about the effects of exercise training (ET) on lexical characteristics during fluency task and its association with cerebellum functional connectivity. The purposes of this study were (1) to investigate whether ET alters response patterns during phonemic and semantic fluency tasks and (2) to assess the association between ET-related changes in cerebellum functional connectivity (FC) and lexical characteristics during fluency tasks. Thirty-five older adults (78.0 ± 7.1 years; 17 mild cognitive impairment (MCI) and 18 healthy cognition (HC)) underwent a 12-week treadmill ET. Before and after ET, cardiorespiratory fitness tests, phonemic and semantic fluency tests, and resting-state fMRI scans were administered. We utilized a seed-based correlation analysis to measure cerebellum FC and linear regression to assess the association of residualized ET-induced Δcerebellum FC with Δtask performance. Improved mean switches and frequency during the phonemic fluency task were observed following ET in all participants. There were significant associations between ET-induced increases in cerebellum FC and greater phonemic fluency task log frequency, increases in mean switches, and a reduction in the number of syllables in HC. Lastly, there was a significant interaction between group and cerebellar connectivity on phonemic fluency mean log frequency and number of syllables. A 12-week walking ET is related to enhanced phonemic fluency lexical characteristics in older adults with MCI and HC. The association between ET-induced increases in cerebellum FC and enhanced response patterns after ET suggests that the cerebellum may play an important role in ET-related improvement in phonemic fluency performance in cognitively healthy older adults.

Autosomal Recessive Cerebellar Ataxia Type 1: Phenotypic and Genetic Correlation in a Cohort of Chinese Patients with SYNE1 Variants

Abstract: Mutations in the synaptic nuclear envelope protein 1 (SYNE1) gene have been reported to cause autosomal recessive cerebellar ataxia (ARCA) type 1 with highly variable clinical phenotypes. The aim of this study was to describe the phenotypic-genetic spectrum of SYNE1-related ARCA1 patients in the Chinese population. We screened 158 unrelated patients with autosomal recessive or sporadic ataxia for variants in SYNE1 using next-generation sequencing. Pathogenicity assessment of SYNE1 variants was interpreted according to the American College of Medical Genetics standards and guidelines. We identified eight truncating variants and two missense variants spreading throughout the SYNE1 gene from six unrelated families, including nine novel variants and one reported variant. Of the six index patients, two patients showed the classical pure cerebellar ataxia, while four patients exhibited non-cerebellar phenotypes, including motor neuron symptoms, cognitive impairment, or mental retardation. The variants associated with motor neuron or cognition involvement tend to be located in the C-terminal region of SYNE1 protein, compared with the variants related to pure cerebellar ataxia. Our data indicating SYNE1 mutation is one of the more common causes of recessive ataxia in the Chinese population. The use of next-generation sequencing has enabled the rapid analysis of recessive ataxia and further expanded our understanding of genotype-phenotype correlation.