Thomas Hulst

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.

Previous studies on sensorimotor adaptation revealed no awareness of the nature of the perturbation after adaptation to an abrupt 30° 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 naïve, implicit group and a group of subjects using explicit strategies adapted to 20°, 40° and 60° 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° to 60° 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.

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.

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.