The Cerebellum

IntroductionWithin Pediatric Cerebellar Ataxias (PCAs), patients with non-progressive ataxia (NonP) surprisingly show postural motor behavior comparable to that of healthy controls, differently to slow-progressive ataxia patients (SlowP). This difference may depend on the building of the compensatory strategies of the intact areas in NonP brain network. MethodsEleven PCAs patients were recruited: five with NonP and six with SlowP. We assessed volumetric and axonal bundles alterations with a multimodal approach to investigate the connections between basal ganglia and cerebellum as putative compensatory tracts. ResultsCerebellar lobules were smaller in SlowP patients. NonP patients showed a lower number of streamlines in the cerebello-thalamo-cortical tracts but a generalized higher integrity of white matter tracts connecting the cortex and the basal ganglia with the cerebellum. DiscussionThis work reveals that the axonal bundles connecting the cerebellum with basal ganglia and cortex demonstrate a higher integrity in NonP patients. This evidence highlights the importance of the cerebellum-basal ganglia connectivity to explain the different postural motor behavior of NonP and SlowP patients and support the compensatory role of basal ganglia in patients with stable cerebellar malformation.

Background and PurposeBrainstem tumors are rare but cause enduring behavioral issues, challenging patients and surgeons. Research on cerebellar changes in these patients limited, despite symptoms similar to cerebellar injuries. This study aims to investigate cerebellar damage pattern resulting from brainstem tumors and its association with behavioral disorders. MethodsIn this study, a U-Net-based segmentation algorithm was used to divide the cerebellum into 26 lobules, which were then used to build a normative model for assessing individual structural deviations. Furthermore, a behavior prediction model was developed using the total outlier count (tOC) index and brain volume as predictive features. ResultsMost patients were found to have negative deviations in cerebellar regions, particularly in anterior lobules like Left V. Higher tOC was significantly associated with severe social problems (r = 0.31, p = 0.001) and withdrawal behavior (r = 0.28, p = 0.001). Smaller size of cerebellar regions strongly correlated with more pronounced social problems (r = 0.27, p = 0.007) and withdrawal behavior (r = 0.25, p = 0.015). Notably, lobules Right X, V, IV, VIIB, Left IX, VIII, and X influenced social problems, while Left V, Right IV, Vermis VI, and VIII impacted withdrawal behavior. ConclusionsOur study revealed cerebellar damage patterns in patients with brainstem tumors, emphasizing the role of both anterior and posterior cerebellar lobes in social problems and withdrawal behavior. This research sheds light on the brain mechanisms underlying complex behavioral disorders in brainstem tumor patients.

BackgroundNormative childhood motor network resting-state fMRI effective connectivity is undefined, yet necessary for translatable dynamic resting-state network informed treatments in pediatric movement disorders. MethodCross-spectral dynamic causal modelling of resting-state fMRI was investigated in 19 neurotypically developing 5-7-year-old children. Fully connected six-node motor network models were created for each hemisphere including primary motor cortex, striatum, subthalamic nucleus, globus pallidus internus, thalamus, and contralateral cerebellum. Parametric Empirical Bayes with exhaustive Bayesian model reduction and Bayesian modeling averaging were used to create a group model for each hemisphere; Purdue Pegboard Test (PPBT) scores for relevant hand motor behavior were also entered as a covariate at the group level to determine the brain-behavior relationship. ResultsOverall, the resting-state functional MRI effective connectivity of motor cortico-basal ganglia-cerebellar networks was similar across hemispheres, with greater connectivity in the left hemisphere. The motor network effective connectivity relationships between the nodes were consistent and robust across subjects. Additionally, the PPBT score for each hand was positively correlated with the thalamus to contralateral cerebellum connection. DiscussionThe normative effective connectivity from resting-state functional MRI in children largely reflect the direction of inter-nodal signal predicted by other prior modalities and was consistent and robust across subjects, with differences from these prior task-dependent modalities that likely reflect the motor rest-action state during acquisition. Effective connectivity of the motor network was correlated with motor behavior, indicating effective connectivity brain-behavior relationship has physiological meaning in the normally developing. Thus, it may be helpful for future studies in children with movement disorders, wherein comparison to normative effective connectivity will be critical for network-targeted intervention. Impact StatementThis is the first study to use pediatric resting-state functional MRI to create a normative effective connectivity model of the motor network and to also show correlation with behavior, which may have therapeutic implications for children with movement disorders.

BackgroundChristianson syndrome (CS) is an x-linked recessive neurodevelopmental and neurodegenerative condition characterized by severe intellectual disability, cerebellar degeneration, ataxia, and epilepsy. Mutations to the SLC9A6 gene encoding NHE6 are responsible for CS, and we recently demonstrated that a mutation to the rat Slc9a6 gene causes a similar phenotype in the spontaneous shaker rat model, which exhibits cerebellar degeneration with motor dysfunction. In previous work, we used the PhP.eB-L7-Slc9a6-GFP adeno-associated viral (AAV) vector to demonstrate that gene replacement in Purkinje cells reduced the shaker motor and molecular phenotype. MethodsWe carried out a 20-week longitudinal study evaluating the impact of Purkinje cell-specific gene replacement on ataxia and tremor. Taking advantage of the high homology between human SLC9A6 and rat Slc9a6, we tested a more clinically relevant construct, AAV9-CAG-hSLC9A6 AAV vector in the shaker rat. In both experimental cohorts, we performed molecular studies to evaluate expression of NHE6 and key cerebellar markers. We then characterized the relationship between molecular markers and motor function, as well between tremor and ataxia. ResultsAdministration of either of PhP.eB-L7-Slc9a6-GFP or AAV9-CAG-hSLC9A6 AAV vectors led to significant improvement in the molecular and motor phenotypes. The abundance of each disease-relevant cerebellar proteins was significantly correlated to motor ataxia. Further, we found that the relationship between cerebellar ataxia and tremor devolved over time, with disease modifying therapy disrupting their temporal relationship. ConclusionsThese findings impact future SLC9A6-targeted gene therapy efforts for CS and strongly support gene replacement as a viable therapeutic strategy. Furthermore, tremor and ataxia phenotypes may arise from dissociable cerebellar mechanisms. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=69 SRC="FIGDIR/small/621435v2_ufig1.gif" ALT="Figure 1"> View larger version (22K): org.highwire.dtl.DTLVardef@368165org.highwire.dtl.DTLVardef@691b54org.highwire.dtl.DTLVardef@816174org.highwire.dtl.DTLVardef@2508fb_HPS_FORMAT_FIGEXP M_FIG C_FIG

BackgroundSpinocerebellar ataxia type 3 is the most common autosomal dominant inherited ataxia worldwide and is caused by a CAG repeat expansion in the Ataxin-3 gene resulting in a polyQ expansion in the corresponding protein. The disease is characterized by neuropathological (aggregate formation, cell loss), phenotypical (gait instability, body weight reduction), and specific transcriptional changes in affected brain regions. So far, there is no mouse model available representing all the different aspects of the disease, yet highly needed to gain a better understanding of the disease pathomechanism. MethodsHere, we characterized a novel Ataxin-3 knock-in mouse model, expressing either a heterozygous or homozygous expansion of 304 CAG/CAAs in the murine Ataxin-3 locus using biochemical, behavioral, and transcriptomic approaches. Further, we compared the transcriptional changes of the knock-in mice to those found in human SCA3 patients, to evaluate the comparability of our model. ResultsThe novel Ataxin-3 knock-in mouse is characterized by the expression of a polyQ-expansion in the murine Ataxin-3 protein, leading to massive aggregate formation, especially in brain regions known to be vulnerable in SCA3 patients, and impairment of Purkinje cells. Along these neuropathological changes, mice showed a reduction in body weight accompanied by gait and balance instability. Transcriptomic analysis of cerebellar tissue revealed age-dependent differential expression, enriched for genes attributed to myelinating oligodendrocytes. Comparing these transcriptional changes with those found in cerebellar tissue of SCA3 patients, we discovered an overlap of differentially expressed genes pointing towards similar gene expression perturbances in several genes linked to myelin sheaths and myelinating oligodendrocytes. ConclusionThe novel Ataxin-3 knock-in model shares neuropathological, behavioral, and transcriptomic features with human SCA3 patients and, therefore, represents an ideal model to investigate early-onset developments, therapy studies, or longitudinal biomarker alterations.

Cerebellar patients are impaired in motor adaptation. Further, motor adaptation can be divided into a fast component and a slow component, and the cerebellum is known to be especially crucial for the slow component. We tested whether the cerebellar deficit in motor adaptation can be ameliorated by training paradigms targeting slow learning using four visuomotor tasks: standard, gradual, overlearning and long intertrial intervals. We measured slow learning in patients and age-matched controls using a standard paradigm developed for reaching movements by Smith in 2006. The paradigm quantifies slow learning as the magnitude of spontaneous recovery of a previously learned and washed-out adaptation. Cerebellar patients had slower learning and reached a lower level of final adaptation, as seen in previous studies. Nevertheless, both groups had robust spontaneous recovery. Moreover, spontaneous recovery was increased in both groups in the overlearning paradigm with no significant difference between them. Computational modeling suggested that increased spontaneous recovery in the Control group reflects a changed slow adaptation system. That is, in the overlearning in controls, the slow system forgot more slowly and had a slower response to errors. In contrast, the same modeling suggests that no such change in the slow system occurred in the Cerebellar group. Rather, increased spontaneous recovery in this group seems to be the result of greater accumulated slow adaptation in the overlearning. We used our modeling results to predict that overlearning should have slower adaptation in the counterperturbation. Modeling further suggested we would not see these difference in the cerebellar patients. Follow-up analysis confirmed these model predictions. Taken together, our results imply that residual slow learning in cerebellar patients is expressed during increased training trials, but the primary cerebellar deficit is not improved.

BackgroundNeuroinflammation is a recognized pathological characteristic of neurodegenerative diseases. Spinocerebellar ataxia 13 (SCA13) is a progressive neurodegenerative disease with no effective treatments. Our previous studies reported human mutations in KCNC3 gene are causative for SCA13. Human R423H allelic mutation induces early-onset neurodegeneration and aberrant intracellular retention of Epidermal Growth Factor Receptor (EGFR) in drosophila. However, the neurodegeneration and inflammatory response induced by the R424H allele are unknown in a mammalian model of disease. MethodIn this study, a single Kcnc3 R424H mutation (Analogous to the human SCA13 R423H isoform) transgenic mice were created using CRISPR/Cas 9 technique. Motor function (gait, tremor, coordination and balance) and cerebellar volume (scanned and imaged with 7T MRI) of the R424H transgenic mice were evaluated at multiple timepoints. Neurodegeneration (Purkinje cells loss) as well as cerebellar (astroglia, microglia and macrophage activation) and peripheral (plasma cytokines levels) inflammatory responses were examined and analyzed. ResultThe R424H transgenic mice showed marked neurological motor dysfunction with high-frequency tremor, aberrant gait, and short latency to fall in Rotarod testing at 3 and 6 months of age. Abnormal spontaneous firing was recorded in electrophysiology of Purkinje cells. Pathological changes in our R424H transgenic mice included progressive Purkinje cell degeneration and cerebellar atrophy. Over-active microglia, astrocytes, and macrophages were observed in the cerebella of transgenic mice. Pearson correlation analyses indicated that the number of Calbindin positive cells, a Purkinje cell marker, showed a strong inverse correlation with the positive cell number of EGFR, phosphorylated EGFR (pEGFR), and CD68. The expression of EGFR/pEGFR was positively correlated with CD68 and Glial Fibrillary Acidic Protein. ConclusionTransgenic R424H mice provide a novel SCA13 model showing significant motor deficits, Purkinje cells loss, cerebellar inflammation, and atrophy. Our study suggests that the activation of inflammatory immune cells (astroglia, microglia and macrophages) and strong expression of EGFR/ pEGFR signal in these immune cells are associated with Purkinje cell loss in the cerebellum. This abnormal neuroinflammation may play a significant role in the aggressive procession of neurodegeneration.

Background and ObjectivesApproximately 25% of pediatric patients who undergo cerebellar tumor resection develop cerebellar mutism syndrome (CMS). Our group recently showed that damage to the cerebellar outflow pathway is associated with increased risk of CMS. Here, we tested whether these findings replicate in an independent cohort. MethodsWe evaluated the relationship between lesion location and the development of CMS in an observational study of 56 pediatric patients who underwent cerebellar tumor resection. We hypothesized that individuals that developed CMS after surgery (CMS+), relative to those that did not (CMS-) would have lesions that preferentially intersected with: 1) the cerebellar outflow pathway, and 2) a previously generated lesion-symptom map of CMS. Analyses were conducted in accordance with pre-registered hypotheses and analytic methods (https://osf.io/r8yjv/). ResultsWe found supporting evidence for both hypotheses. Compared with CMS-patients, CMS+ patients (n=10) had lesions with greater overlap with the cerebellar outflow pathway (Cohens d=.73, p=.05), and the CMS lesion-symptom map (Cohens d=1.1, p=.004). DiscussionThese results strengthen the association of lesion location with risk of developing CMS and demonstrate generalizability across cohorts. These findings may help to inform the optimal surgical approach to pediatric cerebellar tumors.

BackgroundFatigue is multifactorial and task-dependent, arising from the interplay between performance and perceived fatigability. Fatigue-related changes in sensorimotor control and neural activity may alter skill acquisition and retention. ObjectiveTo synthesize behavioral and neurophysiological evidence on how cognitive, cardiovascular, and neuromuscular fatigue influence motor-skill acquisition, consolidation/retention, and transfer. MethodsA systematic search was conducted within PubMed, Web of Science, and Embase. Thirty-four studies (39 experiments) met inclusion criteria (fatigue effects on motor learning in non-disabled participants). Data were extracted on fatigue protocol, learning taxonomy, learning stage (acquisition vs. retention/transfer), interval, and neurophysiology. Methodological quality was appraised with a tailored Downs & Black checklist. ResultsDuring acquisition, 64% of experiments reported impairments under fatigue, particularly for visuomotor precision and fine force control; 10% found facilitation (often after cardiovascular exertion or high cognitive load); 15% were neutral; 10% inconclusive. Retention was tested in a fresh state and in a fatigue state in 34 experiments and 6 experiments, respectively. Results during retention tests were relatively variable, depending on fatigue protocols. Neurophysiological measures were scarce (EEG/TMS in only four studies), and very few studies considered the effects of personal factors such as age or sex. ConclusionsFatigue does not uniformly impair motor learning. Neuromuscular fatigue typically hampers acquisition and sometimes retention, while cardiovascular exertion can transiently prime plasticity and enhance consolidation. Evidence for cognitive fatigue is limited and inconsistent. Future work should use longer retention windows, state-matched testing, and integrated neurophysiology to clarify mechanisms and guide training under fatigue.

The development of the cerebellum starts from early gestational period and extends postnatal. Because of its protracted development, the cerebellum is susceptible to developmental anomalies such as Dandy-Walker malformations, Blakes pouch cysts and vermin hypoplasia. Measurements of fetal cerebellar parameters of a normal growing fetus in each week of gestation is important for setting up morphometric standards and hence used as clinical reference data. Any deviation from the normal cerebellar parameters alerts the clinicians for the possibility of presence of cerebellar malformations. Study objectiveThe objective of this study was to assess the fetal cerebellar growth by quantifying the following parameters; fetal cerebellar volume, anterior-posterior diameter and superior-inferior diameter. MethodsWe used 3T and 7T MRI to scan the postmortem fetal brains at different stages of development and subsequently analyze the images using ITK-SNAP software. ResultsThe mean superior-inferior cerebellar diameter was found to be 19.12{+/-}2. 70mm.The linear(y=bo+b1t) model was the best fit (r2=0.996, F=32022.961) to describe the relationship between the gestational age and the superior-inferior diameter(y=5.89+0.49t). There was significant correlation between the superior-inferior cerebellar diameter and the gestation age, Pearson correlation coefficient of 0.999, r=0.001. The median cerebellar volume was 8607.7mm, the mean rank high among males(78.12) as compared to female(68.25).There was no statistically significant difference of the cerebellar volume between males and females (u=2193.5,p=0.16).The quadratic(y=bo+b1t+b2t2) model was the best fit regression equation (r2=0.994,F=10791.157) describing the relationship between the cerebellar volume and the gestational age. The median anterior- posterior diameter was 12.45 mm. There was significant correlation between anterior-posterior diameter and the gestational age with Spearmans rho of (0.997, p=0.01). The linear model was the best fit the best fit model (y=bo+b1t) describing the relationship between anterior-posterior diameter and the gestational age(y=3.31+0.5t) r2=0.998, F=70646.838 ConclusionSignificant correlation between the superior-inferior cerebellar diameters, the anterior-posterior cerebellar diameter and the gestational age was found. These two linear parameters follow the first-degree polynomial in relation to the gestational age. The cerebellar volume follows the second-degree polynomial as it increases with the gestational age and correlate significantly with the gestational age. This study has provided new insight to the development of the cerebellum, and setup a benchmark data of which the deviation from it will alert the clinicians for the possibility of presence of cerebellar malformations.

Cerebellar dysfunction causes various movement disorders, including ataxia, dystonia, and tremor. Previous work demonstrated that spike patterns in cerebellar nuclei neurons were distinct between different movement disorder mouse models. However, often these changes arise from neural dysfunction in the cerebellar cortex, through misfiring, miswiring, or degenerating Purkinje cells. Even though Purkinje cells form the sole output from the cerebellar cortex, their information is relayed to other regions of the motor network via cerebellar nuclei cells. Purkinje cells make GABAergic synapses onto cerebellar nuclei cells, and it is often assumed that changes in Purkinje cell spike patterns result in inverse changes in nuclei cell spike patterns. Here, we test this hypothesis by answering the question of whether a reliable relationship between Purkinje cell and nuclei cell spike patterns exists. Single-cell, in vivo electrophysiology recordings of both cell types from six mouse models for cerebellar movement disorders were analyzed according to parameters relating to spike rate and irregularity. We investigated whether Purkinje cell spike patterns correlated with nuclei cell spike patterns. We found that some parameters for firing irregularity were positively correlated between Purkinje and nuclei cells but no - and particularly no inverse - relationship was observed between Purkinje and nuclei cell spike rate. Overall, this study begins to illuminate that the relationship between Purkinje cells and nuclei cell spike activity in a disease state is more complex and unpredictable. The data suggest Purkinje cell spike activity changes cannot accurately predict nuclei cell changes, which ultimately drive cerebellar disease states. Our findings underscore the importance of studying cerebellar nuclei cell function in cerebellar disease, as lack of changes in Purkinje cell firing patterns can mask disease-causing firing patterns in these cerebellar output cells.

PurposeTo explore the effect of joint hypermobility on acuity, and plasticity, of hand proprioception. Materials and MethodsWe compared proprioceptive acuity between EDS patients and controls. We then measured any changes in their estimate of hand position after participants adapted their reaches in response to altered visual feedback of their hand. The Beighton Scale was used to quantify the magnitude of joint hypermobility. ResultsThere were no differences between the groups in the accuracy of estimates of hand location, nor in the visually-induced changes in hand location. However, EDS patients estimates were less precise when based purely on proprioception and could be partially predicted by Beighton score. ConclusionsEDS patients are less precise at estimating their hands location when only afferent information is available, but the presence of efferent signalling may reduce this imprecision. Those who are more hypermobile are more likely to be imprecise.

BackgroundThe entopeduncular nucleus (EP), corresponding to the human globus pallidus internal segment, is a basal ganglia output nucleus, and plays a critical role in motor control. However, the impact of EP damage on skilled motor function and the relationship between its damage in stroke, such as internal capsule hemorrhage (ICH), and motor dysfunction remains unclear. This study aimed to clarify whether EP damage causes motor dysfunction in two disease models. MethodsEP-related motor dysfunction was investigated by inducing localized unilateral EP damage in Long-Evans rats using a stereotactic kainic acid (KA) injection. Motor function was assessed using a single-pellet reaching task pre-injection and on postoperative days 2, 7, 14, 21, and 28. Immunohistochemical staining for NeuN, somatostatin (SST), and parvalbumin was conducted to quantify damage and its correlation with motor outcomes. In addition, unilateral ICH was induced via stereotactic injection of collagenase type IV, which dissolves the vascular basement membrane, into the internal capsule (IC) of Long-Evans rats. Injury sites were classified into the IC, dorsomedial region from the IC, ventral lateral region from the IC, and EP, and their volumes were measured. Measured volumes were analyzed for correlations with motor function assessments. ResultsKA-induced EP damage significantly reduced reaching success rates on postoperative day 2 compared to those in the control group (p<0.05). Immunohistochemical analysis showed that reaching success rates on day 28 positively correlated with the numbers of remaining NeuN-positive and SST-positive neurons (p<0.05). In the ICH experiment, all rats significantly reduced the success rate of the reaching task to 0% on day 2, and the success rate on day 28 correlated positively with the remaining EP volume, but not with total lesion volume. ConclusionsEP damage was strongly associated with motor impairments, highlighting its critical role in motor control and recovery.

Cerebellar ataxias are a rare group of disorders manifesting with motor incoordination and cognitive-affective deficits of variable severity. Although neurogenetic has revealed multiple mutations, the study of ataxias still relies on clinical evaluation, while the underlying neural network changes remain unclear. It has been argued that the less severe symptoms in congenital (like Joubert syndrome, JS) than in slowly progressive (SP) ataxias reflect a different interplay of alteration and compensation but direct evidence is still lacking. Moreover, it is unclear why, in front of a wide heterogeneity of molecular alterations, SPs show common clinical symptoms. To address these questions, we created brain digital twins for each participant by combining volumetry, graph theory analysis of structural and functional connectivity, and dynamical simulations using the virtual brain. We studied 8 JS (3 females, 21{+/-}6years), 8 SP (3 females, 20{+/-}5years) and 11 healthy controls (HC; 5 females, 21{+/-}2years).Volumetry quantified atrophy, graph metrics (centrality, segregation and integration) characterized topology, and neural dynamical simulations estimated excitation/inhibition balance, providing anatomo-physiological parameters within the somatomotor (SMN) and ventral attention (VAN) networks. Anatomo-physiological parameters were correlated with clinical/neuropsychological scores, and unsupervised clustering was applied to assess whether network features can discriminate between JS and SP beyond clinical classification. MRI morphometry confirmed selective vermis reduction in JS and a widespread cerebellar atrophy in SP compared to HC. In both ataxia groups, SMN and VAN showed reduced volume and structural connectivity but with different patterns of topological and dynamical alterations. In the SMN of SP, reduced centrality and excitation/inhibition balance depressed information transfer through the network. In the VAN of JS, reduced centrality, segregation, and integration, were detrimental but coexisted with a higher number of functional core nodes and an increased large-scale excitatory coupling, supporting compensatory reorganisation in extracerebellar nodes. Clustering confirmed that SMN better differentiates SP, whereas VAN better clusters JS. Importantly, anatomo-physiological parameters of network volume, topology, and dynamics correlated with patients motor and cognitive performance. In conclusion, primary cerebellar damage secondarily impacts large-scale brain networks, altered in both ataxia groups but compensated only in JS. Similar clinical symptoms in SP reflects the similarity of network changes, while differential involvement of SMN and VAN in JS and SP reflects the connectivity pattern of the lesioned areas inside these large-scale brain circuits. Importantly, anatomo-physiological parameters are sufficient to explain individual motor and cognitive performance, offering a basis for improved patient profiling and personalized therapies.

BackgroundSpinocerebellar ataxia (SCA) is a degenerative cerebellar disease, causing progressive impairment of gait and balance in adults. To identify the ideal subjects for disease-modifying therapies it is critical to identify biomarkers for the earliest stages of SCA. ObjectiveWe investigated whether prefrontal cortex activity is increased during walking in in early SCA or in pre-manifest SCA compared to healthy control subjects. MethodsSixteen participants with genetically determined SCA and 15 age-matched healthy controls participated in the study. The SARA was administered by a movement disorders specialist before the gait assessment. An 8-channel, mobile, fNIRS, with two reference channels, was used to record changes in oxygenated hemoglobin (HbO2) and deoxygenated hemoglobin within the PFC. Participants walked for 2-minutes at a comfortable pace while wearing wireless, inertial sensors to derive gait characteristics. ResultsOf the 16 individuals with SCA, 9 were classified as pre-manifest (SARA<3) and 7 as early SCA (SARA<10). PFC activity (HbO2) while walking was greater than controls of similar age in people with SCA. Increased PFC activity was also present even in the pre-manifest stage of SCA. Increase in PFC activity was related to worse gait (double-support time and toe-out angle). ConclusionsPFC activity is increased in pre-manifest SCA, even when clinical scores are normal in the pre-manifest stage of the disease, and may serve as a biomarker that precedes onset of clinical disease. Increased PFC activity is consistent less automatic, cortical control of gait to compensate for impaired automatic, cerebellar control, even in early stages of ataxia.

Spinocerebellar Ataxia Type 14 (SCA14) is an autosomal dominant neurodegenerative disease caused by mutations in the gene encoding protein kinase C gamma (PKC{gamma}), a Ca2+/diacylglycerol (DG)-dependent serine/threonine kinase dominantly expressed in cerebellar Purkinje cells. These mutations impair autoinhibitory constraints to increase the basal activity of the kinase, resulting in deficits in the cerebellum that are not observed upon simple deletion of the gene, and severe ataxia. To better understand the phenotypic impact of aberrant PKC{gamma} signaling in disease pathology, we developed a knock-in murine model of the SCA14 mutation {Delta}F48 in PKC{gamma}. This fully penetrant mutation is severe in humans and is mechanistically informative as it has high basal activity but is unresponsive to agonist stimulation. Genetic, behavioral, and molecular testing revealed that {Delta}F48 PKC{gamma} SCA14 mice have ataxia related phenotypes and an altered cerebellar phosphoproteome, effects that are more severe in male mice. Analysis of existing human data reveal that SCA14 has a significantly earlier age of onset for males compared with females. Our data from this clinically relevant mutation suggest that enhanced basal activity of PKC{gamma} is necessary and sufficient to cause ataxia and that treatment strategies to modulate aberrant PKC{gamma} may be particularly beneficial in males. SummaryNew mouse model of Spinocerebellar Ataxia Type 14 containing a clinically relevant mutation in PKC{gamma} identified underlying drivers of the disease and neuroprotection in females.

Research has investigated the use of non-invasive brain interventions, such as transcranial direct current stimulation (tDCS), to enhance motor learning and rehabilitation. Much research has shown that tDCS improves motor learning and that bilateral tDCS is more beneficial than unilateral tDCS in improving motor learning. However, past research has primarily utilised simple motor tasks in measuring motor skill learning. These are not ecologically reliable as whole-body movement is required for everyday activities. This study involved two experiments. Each experiment involved participants learning 12 Ballroom and Latin dance moves whilst undergoing tDCS. All participants underwent three sessions of tDCS, (unilateral, bilateral and sham), over three consecutive days. Participants in the first experiment (n=30) had stimulation to the primary motor cortex (PMC) and those in the second experiment (n=31) had stimulation to the dorsolateral prefrontal cortex (DLPFC). In each experiment, a baseline was taken before the training sessions and two outcome measures were taken; a day after the last training session and two weeks later. In each testing session participants dance ability was measured. Our results showed that bilateral tDCS impaired performance in both experiments. Unilateral stimulation impaired performance in the first experiment, and did not significantly improve performance any better than the sham stimulation in the second experiment. These results suggest that task complexity plays a crucial role when tDCS procedures are used to modulate motor performance and highlights possible limitations of tDCS in practice.

Cerebellar ataxia is associated with an implicit motor learning dysfunction, specifically, a miscalibration of internal models relating motor commands to state changes of the body. Explicit cognitive strategies could compensate for deficits in implicit calibration. Surprisingly, however, patients with cerebellar ataxia use insufficient strategies compared to healthy controls. We report a candidate physiological phenomenon of disrupted strategy use in cerebellar ataxia, reflected in an interaction of implicit and explicit learning effects on cortical beta oscillations. We recorded electroencephalography in patients with cerebellar ataxia (n=18), age-matched healthy controls (n=19), and young, healthy individuals (n=34) during a visuomotor rotation paradigm in which an aiming strategy was either explicitly instructed, or had to be discovered through learning. In young, healthy individuals, learning a strategy, but not implicit learning from sensory prediction error alone, decreased the post-movement beta rebound. Disrupted learning from sensory prediction error in patients, on the other hand, unmasked effects of explicit and implicit control that are normally balanced. Specifically, the post-movement beta rebound increased during strategy use when implicit learning was disrupted, i.e., in patients, but not controls. We conclude that a network disturbance due to cerebellar degeneration surfaces in imbalanced cortical beta oscillations normally involved in strategy learning.

OBJECTIVESWith disease-modifying drugs for degenerative ataxias on the horizon, ecologically valid measures of motor performance that can detect patient-relevant changes in short, trial-like time frames are highly warranted. In this 2-year longitudinal study, we aimed to unravel and evaluate measures of ataxic gait which are sensitive to longitudinal changes in patients real life by using wearable sensors. METHODSWe assessed longitudinal gait changes of 26 participants with degenerative cerebellar disease (SARA:9.4{+/-}4.1) at baseline, 1-year and 2-year follow-up assessment using 3 body-worn inertial sensors in two conditions: (1) laboratory-based walking (LBW); (2) real-life walking (RLW) during everyday living. In the RLW condition, a context-sensitive analysis was performed by selecting comparable walking bouts according to macroscopic gait characteristics, namely bout length and number of turns within a two-minute time interval. Movement analysis focussed on measures of spatio-temporal variability, in particular stride length variability, lateral step deviation, and a compound measure of spatial variability (SPCmp). RESULTSGait variability measures showed high test-retest reliability in both walking conditions (ICC > 0.82). Cross-sectional analyses revealed high correlations of gait measures with ataxia severity (SARA, effect size {rho}[&ge;]0.75); and in particular with patients subjective balance confidence (ABC score, {rho}[&ge;]0.71), here achieving higher effect sizes for real-life than lab-based gait measures (e.g. SPCmp: RLW {rho}=0.81 vs LBW {rho}=0.71). While the clinician-reported outcome SARA showed longitudinal changes only after two years, the gait measure SPCmp revealed changes already after one year with high effect size (rprb=0.80). In the subgroup with spinocerebellar ataxia type 1, 2 or 3 (SCA1/2/3), the effect size was even higher (rprb=0.86). Based on these effect sizes, sample size estimation for the gait measure SPCmp showed a required cohort size of n=42 participants (n=38 for SCA1/2/3 subgroup) for detecting a 50% reduction of natural progression after one year by a hypothetical intervention, compared to n=254 for the SARA. CONCLUSIONSGait variability measures revealed high reliability and sensitivity to longitudinal change in both laboratory-based constrained walking as well as in real-life walking. Due to their ecological validity and larger effect sizes, characteristics of real-life gait recordings are promising motor performance measures as outcomes for future treatment trials.

The ability to self-evaluate motor performance or estimate performance errors is beneficial for motor learning or relearning in the context of neurologic injury. Some evidence suggests those with injury like stroke may be unable to accurately self-evaluate their performance; however, it is unclear if individuals who are absent of injury are accurate in this domain. We aimed to investigate the accuracy of self-evaluation and potential influencing factors by conducting a systematic search to identify literature involving the self- and objective-evaluation of upper-extremity motor tasks. Twenty-three studies satisfied inclusion criteria. Data revealed a moderate positive correlation between self- and objective evaluations across a variety of tasks, from trivial button pressing to specialized surgical suturing. Both under- and overestimation of performance was found across the papers. Key factors identified to influence the accuracy of self-evaluation were the task purpose, familiarity, difficulty, and whether an individual received a demonstration. This review identified some limitations in this field of research. Most notably, we found that very few studies have investigated the accuracy of self-evaluation of motor performance with the primary goal of comparison to objective performance. Many studies reported the data but did not make direct statistical comparisons. Moreover, due to inconsistencies between how self and objective-evaluations were conducted, we argue that in this area of investigation self-evaluation tools need to replicate the objective evaluation method, or at minimum the self-evaluation tool should ask questions specific to the construct of performance that is being measured objectively.