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The cerebellar nuclei are a brain region with high iron content. Surprisingly, little is known about iron content in the cerebellar nuclei and its possible contribution to pathology in cerebellar ataxias, with the only exception of Friedreich’s ataxia. In the present exploratory cross-sectional study, quantitative susceptibility mapping was used to investigate volume, iron concentration and total iron content of the dentate nuclei in common types of hereditary and non-hereditary degenerative ataxias. Seventy-nine patients with spinocerebellar ataxias of types 1, 2, 3 and 6; 15 patients with Friedreich’s ataxia; 18 patients with multiple system atrophy, cerebellar type and 111 healthy controls were also included. All underwent 3 T MRI and clinical assessments. For each specific ataxia subtype, voxel-based and volumes-of-interest-based group analyses were performed in comparison with a corresponding age- and sex-matched control group, both for volume, magnetic susceptiblity (indicating iron concentration) and susceptibility mass (indicating total iron content) of the dentate nuclei. Spinocerebellar ataxia of type 1 and multiple system atrophy, cerebellar type patients showed higher susceptibilities in large parts of the dentate nucleus but unaltered susceptibility masses compared with controls. Friedreich’s ataxia patients and, only on a trend level, spinocerebellar ataxia of type 2 patients showed higher susceptibilities in more circumscribed parts of the dentate. In contrast, spinocerebellar ataxia of type 6 patients revealed lower susceptibilities and susceptibility masses compared with controls throughout the dentate nucleus. Spinocerebellar ataxia of type 3 patients showed no significant changes in susceptibility and susceptibility mass. Lower volume of the dentate nuclei was found to varying degrees in all ataxia types. It was most pronounced in spinocerebellar ataxia of type 6 patients and least prominent in spinocerebellar ataxia of type 3 patients. The findings show that alterations in susceptibility revealed by quantitative susceptibility mapping are common in the dentate nuclei in different types of cerebellar ataxias. The most striking changes in susceptibility were found in spinocerebellar ataxia of type 1, multiple system atrophy, cerebellar type and spinocerebellar ataxia of type 6. Because iron content is known to be high in glial cells but not in neurons of the cerebellar nuclei, the higher susceptibility in spinocerebellar ataxia of type 1 and multiple system atrophy, cerebellar type may be explained by a reduction of neurons (increase in iron concentration) and/or an increase in iron-rich glial cells, e.g. microgliosis. Hypomyelination also leads to higher susceptibility and could also contribute. The lower susceptibility in SCA6 suggests a loss of iron-rich glial cells. Quantitative susceptibility maps warrant future studies of iron content and iron-rich cells in ataxias to gain a more comprehensive understanding of the pathogenesis of these diseases.

We tested whether training paradigms targeting slow learning alleviate motor learning deficits of cerebellar patients compared to matched controls using four visuomotor tasks: standard, gradual, overlearning and long intertrial interval. We measured slow learning using spontaneous recovery, the return to learned adaptation after brief wash out of fast adaptation. Spontaneous recovery increased in both groups only in overlearning. A model of adaptation suggested that in controls the increase reflects changes in slow system dynamics. In contrast, because cerebellar participants plateaued more slowly than controls, added trials in models of cerebellar participants increased the level of slow learning. Whereas, under the model, slow learning became more resilient in controls, there was no change in its dynamics for cerebellar participants. Our results and modeling suggest that while residual slow learning does exist in cerebellar patients and can be expressed through increased training trials, the primary cerebellar deficit cannot be improved by overlearning paradigms.

In the present study extinction and renewal of cognitive associations were assessed in two experiments in participants with focal and degenerative cerebellar disease. Using a predictive learning task, participants had to learn by trial and error the relationships between food items and the occurrence of stomach trouble in a hypothetical patient. In the first experiment, focus was on renewal effects. Participants with chronic cerebellar stroke (n = 14; mean age 50.9 ± 12 years), participants with degenerative cerebellar disease (n = 16; mean age 58 ± 12 years), age-, sex-, and education matched controls (n = 20; mean age 53.7 ± 10.8 years) and young controls (n = 19; mean age 23.2 ± 2.7 years) were tested. Acquisition and extinction of food-stomach trouble associations took part in two different contexts (represented by restaurants). In a subsequent test phase, food stimuli were presented in both contexts and no feedback was given. This allowed testing for renewal of the initially acquired associations in the acquisition context. Acquisition and extinction learning were not significantly different between groups. Significant renewal effects were present in young controls only. In the second experiment, focus was on extinction. To control for age effects, 19 young participants with chronic surgical lesions of the cerebellum (mean age 25.6 ± 6.1 years), and 24 age-, sex- and education-matched healthy controls were tested. Acquisition and extinction of food-stomach trouble associations took part in the same context. In the extinction phase, the relationship with stomach trouble was reversed in some of the food items. Acquisition and extinction learning were not significantly different between groups. The main finding of the present study was preserved extinction of learned cognitive associations in participants with chronic cerebellar disease. Findings agree with previous observations in the literature that cognitive abnormalities are frequently absent or weak in adults with cerebellar disease. This does not exclude a contribution of the cerebellum to extinction of learned associations. For example, findings may be different in more challenging cognitive tasks, and in participants with acute cerebellar disease with no time for compensation.

Cerebellar transcranial direct current stimulation (tDCS) has been reported to enhance the acquisition of conditioned eyeblink responses (CR), a form of associative motor learning. The aim of the present study was to determine possible long-term effects of cerebellar tDCS on the acquisition and extinction of CRs. Delay eyeblink conditioning was performed in 40 young and healthy human participants. On day 1, 100 paired CS (conditioned stimulus)–US (unconditioned stimulus) trials were applied. During the first 50 paired CS–US trials, 20 participants received anodal cerebellar tDCS, and 20 participants received sham stimulation. On days 2, 8 and 29, 50 paired CS–US trials were applied, followed by 30 CS-only extinction trials on day 29. CR acquisition was not significantly different between anodal and sham groups. During extinction, CR incidences were significantly reduced in the anodal group compared to sham, indicating reduced retention. In the anodal group, learning related increase of CR magnitude tended to be reduced, and timing of CRs tended to be delayed. The present data do not confirm previous findings of enhanced acquisition of CRs induced by anodal cerebellar tDCS. Rather, the present findings suggest a detrimental effect of anodal cerebellar tDCS on CR retention and possibly CR performance.

Previous studies have shown that cerebellar transcranial direct current stimulation (tDCS) leads to faster adaptation of arm reaching movements to visuomotor rotation and force field perturbations in healthy subjects. The first aim of the present study was to confirm a stimulation-dependent effect on motor adaptation. Second, we investigated whether tDCS effects differ depending on onset, that is, before or at the beginning of the adaptation phase. A total of 120 healthy and right-handed subjects (60 women, mean age 23.2 ± SD 2.7 yr, range 18–31 yr) were tested. Subjects moved a cursor with a manipulandum to one of eight targets presented on a vertically orientated screen. Three baseline blocks were followed by one adaptation block and three washout blocks. Sixty subjects did a force field adaptation task (FF), and 60 subjects did a visuomotor adaptation task (VM). Equal numbers of subjects received anodal, cathodal, or sham cerebellar tDCS beginning either in the third baseline block or at the start of the adaptation block. In FF and VM, tDCS and the onset of tDCS did not show a significant effect on motor adaptation (all P values >0.05). We were unable to support previous findings of modulatory cerebellar tDCS effects in reaching adaptation tasks in healthy subjects. Prior to possible application in patients with cerebellar disease, future experiments are needed to determine which tDCS and task parameters lead to robust tDCS effects. NEW & NOTEWORTHY Transcranial direct current stimulation (tDCS) is a promising tool to improve motor learning. We investigated whether cerebellar tDCS improves motor learning in force field and visuomotor tasks in healthy subjects and what influence the onset of stimulation has. We did not find stimulation effects of tDCS or an effect of onset of stimulation. A reevaluation of cerebellar tDCS in healthy subjects and at the end of the clinical potential in cerebellar patients is demanded.

Autism spectrum disorder is a developmental disorder characterized by deficits in social and communication skills and repetitive and stereotyped interests and behaviours. Although not part of the diagnostic criteria, individuals with autism experience a host of motor impairments, potentially due to abnormalities in how they learn motor control throughout development. Here, we used behavioural techniques to quantify motor learning in autism spectrum disorder, and structural brain imaging to investigate the neural basis of that learning in the cerebellum. Twenty children with autism spectrum disorder and 20 typically developing control subjects, aged 8-12, made reaching movements while holding the handle of a robotic manipulandum. In random trials the reach was perturbed, resulting in errors that were sensed through vision and proprioception. The brain learned from these errors and altered the motor commands on the subsequent reach. We measured learning from error as a function of the sensory modality of that error, and found that children with autism spectrum disorder outperformed typically developing children when learning from errors that were sensed through proprioception, but underperformed typically developing children when learning from errors that were sensed through vision. Previous work had shown that this learning depends on the integrity of a region in the anterior cerebellum. Here we found that the anterior cerebellum, extending into lobule VI, and parts of lobule VIII were smaller than normal in children with autism spectrum disorder, with a volume that was predicted by the pattern of learning from visual and proprioceptive errors. We suggest that the abnormal patterns of motor learning in children with autism spectrum disorder, showing an increased sensitivity to proprioceptive error and a decreased sensitivity to visual error, may be associated with abnormalities in the cerebellum.

Background: The control of grip forces when moving a hand held object is impaired in patients with cerebellar degeneration. We asked the question whether after-effects of anodal transcranial direct current stimulation (tDCS) applied to the lateral cerebellum or M1 improved grip force control in cerebellar patients. Methods: Grip force control while holding an object during cyclic arm movements was assessed in patients with pure cerebellar degeneration (n = 14, mean age 50.2 years ± SD 8.8 years) and age- and sex-matched control participants (n = 14, mean age 50.7 years ± SD 9.8 years). All subjects were tested before and after application of tDCS (2 mA, 22 min) in a within-subject design. Each subject received anodal tDCS applied to the cerebellum, anodal tDCS applied to M1 or sham-stimulation with a break of 1 week between the three experimental sessions. Results: There were no clear after-effects of tDCS on grip force control neither in control participants nor in cerebellar patients. Cerebellar patients showed typical impairments with higher grip forces, a higher variability of movements. Conclusion: In the present study, deficits in grip force control were neither improved by tDCS applied over the cerebellum nor M1 in cerebellar degeneration.

Transcranial direct current stimulation (tDCS) has been identified as a potential tool in the rehabilitation of cerebellar disease. We investigated whether tDCS of the cerebellum and primary motor cortex could alleviate motor impairments of subjects with cerebellar degeneration. The present study did not find stimulation effects of tDCS in young controls, aging controls, and individuals with cerebellar degeneration during reach adaptation. Our results require a re-evaluation of the clinical potential of tDCS in cerebellar patients.Several studies have identified transcranial direct current stimulation (tDCS) as a potential tool in the rehabilitation of cerebellar disease. Here, we tested whether tDCS could alleviate motor impairments of subjects with cerebellar degeneration. Three groups took part in this study: 20 individuals with cerebellar degeneration, 20 age-matched controls, and 30 young controls. A standard reaching task with force-field perturbations was used to compare motor adaptation among groups and to measure the effect of stimulation of the cerebellum or primary motor cortex (M1). Cerebellar subjects and age-matched controls were tested during each stimulation type (cerebellum, M1, and sham) with a break of 1 wk among each of the three sessions. Young controls were tested during one session under one of three stimulation types (anodal cerebellum, cathodal cerebellum, or sham). As expected, individuals with cerebellar degeneration had a reduced ability to adapt to motor perturbations. Importantly, cerebellar patients did not benefit from anodal stimulation of the cerebellum or M1. Furthermore, no stimulation effects could be detected in aging and young controls. The present null results cannot exclude more subtle tDCS effects in larger subject populations and between-subject designs. Moreover, it is still possible that tDCS affects motor adaptation in cerebellar subjects and control subjects under a different task or with alternative stimulation parameters. However, for tDCS to become a valuable tool in the neurorehabilitation of cerebellar disease, stimulation effects should be present in group sizes commonly used in this rare patient population and be more consistent and predictable across subjects and tasks.

Introduction Studies with transcranial direct current stimulation (tDCS) have shown that anodal tDCS of the cerebellar hemispheres leads to faster adaptation of arm reaching movements to visuomotor rotation and force field perturbations in healthy subjects ( Galea et al., 2011 , Herzfeld, 2014 ). Objectives The first aim of the present study was to replicate the findings mentioned above. The second aim was to investigate whether tDCS effects differ depending on the onset of stimulation, that is during or after an initial baseline phase. Patients and Methods A total of 120 healthy and right-handed subjects (60 females, aged 18–31 years, mean 23.2 ± 2.7) were tested. Subjects moved a cursor with a two-joined manipulandum to one of eight targets presented on a screen. There were three baseline blocks, one adaptation block and three washout blocks. 60 subjects performed a force field (FF) task, 60 subjects a visuomotor adaptation task (VM). During the adaptation block, a velocity-dependent clockwise perpendicular force (23 N ·m−1·s−1 was applied in FF and a 30° clockwise rotation in VM. Equal numbers of subjects received anodal, cathodal or sham stimulation over the right cerebellum beginning either in the third baseline or in the adaptation block. The maximum error (ME), final error (FE) and perpendicular velocity 55 ms after movement onset (PV) were assessed. Results During FF and VM adaptation subjects significantly improved regarding ME, FE and PV (p 0.05). The same was true for the washout blocks. Conclusion Our results show that prior possible clinical application, future experiments are needed to determine which cerebellar tDCS and task parameters lead to robust tDCS effects. Funded by ELAN and DFG TI 239/16-1.

Introduction Transcranial direct current stimulation (tDCS) is a non-invasive brain-stimulation technique that can alter cortical excitability and plasticity. Previous studies have shown that anodal tDCS of the cerebellar hemispheres leads to faster adaptation of arm reaching movements to visuomotor rotation and force field perturbations in healthy subjects ( Galea et al., 2011 , Herzfeld et al., 2014 ). The first aim of the present study was to replicate these findings in a force field reaching adaptation task. The second aim was to investigate whether tDCS effects differ depending on onset of stimulation. Methods 60 healthy and right-handed subjects (30 females, aged 20–31 years, mean 24.1 ± 2.3) were tested. Subjects held a two-joined manipulandum with their right hand. They moved a cursor from a central origin to one of eight targets presented on a vertical screen. Three baseline blocks were followed by one adaptation block and three post-adaptation blocks. During adaptation a velocity-dependent clockwise perpendicular force (23 N·m−1·s−1) was applied. tDCS electrodes (5 × 5 cm2) were centered 3 cm lateral to the inion on the right and on the ipsilateral buccinator muscle. An equal number of subjects received anodal, cathodal or sham stimulation during adaptation using a Neuroconn® DC stimulator. tDCS started either in the third baseline block or at the beginning of the adaptation block. The maximum error, the final error and the perpendicular velocity shortly after movement onset (after 55 ms) were assessed. Results During adaptation all subjects showed significant effects of learning. They reduced the maximum error as well as the final error and changed the sign of the perpendicular velocity shortly after movement onset (p 0.05). During post-adaptation, there were significant after- and washout effects. Again, there were no significant effects of stimulation, no significant effects of onset of stimulation and no significant interactions (all p-values > 0.05). Conclusions We were unable to replicate previous findings of modulatory cerebellar tDCS effects in a force field reaching adaptation task in healthy subjects. Furthermore, no differential effects of the onset of stimulation were observed. Prior possible application in patients with cerebellar disease, future experiments are needed to determine which tDCS and task parameters lead to robust tDCS effects. Funded by ELAN (Essener Ausbildungsprogramm “Labor und Wissenschaft” fur den aerztlichen Nachwuchs) and DFG TI 239/16-1

Previous studies on sensorimotor adaptation revealed no awareness of the nature of the perturbation after adaptation to an abrupt 30 degrees rotation of visual feedback or after adaptation to gradually introduced perturbations. Whether the degree of awareness depends on the magnitude of the perturbation, though, has as yet not been tested. Instead of using questionnaires, as was often done in previous work, the present study used a process dissociation procedure to measure awareness and unawareness. A naive, implicit group and a group of subjects using explicit strategies adapted to 20 degrees, 40 degrees and 60 degrees cursor rotations in different adaptation blocks that were each followed by determination of awareness and unawareness indices. The awareness index differed between groups and increased from 20 degrees to 60 degrees adaptation. In contrast, there was no group difference for the unawareness index, but it also depended on the size of the rotation. Early adaptation varied between groups and correlated with awareness: The more awareness a participant had developed the more the person adapted in the beginning of the adaptation block. In addition, there was a significant group difference for savings but it did not correlate with awareness. Our findings suggest that awareness depends on perturbation size and that aware and strategic processes are differentially involved during adaptation and savings. Moreover, the use of the process dissociation procedure opens the opportunity to determine awareness and unawareness indices in future sensorimotor adaptation research.

Ageing generally leads to impairments in cognitive function and the ability to execute and learn new movements. While the causes of these impairments are often multi-factorial, integrity of the cerebellum in an elderly population is an important predictive factor of both motor function and cognitive function. A similar association between cerebellar integrity and function is true for cerebellar patients. We set out to investigate the analogies between the pattern of cerebellar degeneration of a healthy ageing population and cerebellar patients. We quantified cerebellar regional volumes by applying voxel-based morphometry (VBM) to a publicly available dataset of MR images obtained in 313 healthy subjects aged between 18 and 96 years and a dataset of MR images of 21 cerebellar patients. We observed considerable overlap in regions with the strongest loss of cerebellar volume in the two datasets. In both datasets, the anterior lobe of the cerebellum(lobules I-V) and parts of the superior cerebellum( primarily lobule VI) showed the strongest degeneration of cerebellar volume. However, the most significant voxels in cerebellar patients were shifted posteriorly (lobule VII) compared to the voxels that degenerate most with age in the healthy population. The results showed a pattern of significant degeneration of the posterior motor region (lobule VIIIb) in both groups, and significant degeneration of lobule IX and X in the healthy population, but not in cerebellar patients. Furthermore, we saw strong volumetric degeneration of functionally defined cerebellar regions associated with cerebral somatomotor function in both groups. Predominance of degeneration in the anterior lobe and lobule VI suggests impairment of motor function in both groups, while we suggest that the posterior shift of degeneration in cerebellar patients would be associated with relatively stronger impairment of higher motor function and cognitive function. Thus, these results may explain the specific symptomology associated with cerebellar degeneration in ageing and in cerebellar patients. (C) 2015 Elsevier Inc. All rights reserved.