Lack of cerebellar tDCS effects on learning of a complex whole body dynamic balance task in middle-aged (50-65 years) adults.

BACKGROUND: Cerebellar transcranial direct current stimulation (tDCS) is widely considered as a promising non-invasive tool to foster motor performance and learning in health and disease. The results of previous studies, however, are inconsistent. Our group failed to provide evidence for an effect of cerebellar tDCS on learning of a complex whole body dynamic balance task in young and healthy participants. Ceiling effects in the young study population are one possible explanation for the negative findings. METHODS: In the present study, we therefore tested 40 middle-aged healthy participants between the ages of 50 to 65 years. Participants received either anodal or sham cerebellar tDCS using a double-blinded study design while performing a balance task on a Lafayette Instrument 16,030 stability platform®. Mean platform angle and mean balance time were assessed as outcome measures. RESULTS: Significant learning effects were found in all participants. Balancing performance and learning rate was significantly less in the group of middle-aged adults compared to our previous group of young adults. No significant effects of cerebellar tDCS were observed. CONCLUSIONS: Our findings are in line with other studies that have failed to prove robust effects of cerebellar tDCS on motor learning. The present findings, however, do not exclude cerebellar tDCS effects. tDCS effects may be more prominent after repeated stimulation, using other stimulus parameters, in patient populations, or in other motor learning tasks. TRIAL REGISTRATION: Not applicable.

Consensus Paper: Neurophysiological Assessments of Ataxias in Daily Practice.

The purpose of this consensus paper is to review electrophysiological abnormalities and to provide a guideline of neurophysiological assessments in cerebellar ataxias. All authors agree that standard electrophysiological methods should be systematically applied in all cases of ataxia to reveal accompanying peripheral neuropathy, the involvement of the dorsal columns, pyramidal tracts and the brainstem. Electroencephalography should also be considered, although findings are frequently non-specific. Electrophysiology helps define the neuronal systems affected by the disease in an individual patient and to understand the phenotypes of the different types of ataxia on a more general level. As yet, there is no established electrophysiological measure which is sensitive and specific of cerebellar dysfunction in ataxias. The authors agree that cerebellar brain inhibition (CBI), which is based on a paired-pulse transcranial magnetic stimulation (TMS) paradigm assessing cerebellar-cortical connectivity, is likely a useful measure of cerebellar function. Although its role in the investigation and diagnoses of different types of ataxias is unclear, it will be of interest to study its utility in this type of conditions. The authors agree that detailed clinical examination reveals core features of ataxia (i.e., dysarthria, truncal, gait and limb ataxia, oculomotor dysfunction) and is sufficient for formulating a differential diagnosis. Clinical assessment of oculomotor function, especially saccades and the vestibulo-ocular reflex (VOR) which are most easily examined both at the bedside and with quantitative testing techniques, is of particular help for differential diagnosis in many cases. Pure clinical measures, however, are not sensitive enough to reveal minute fluctuations or early treatment response as most relevant for pre-clinical stages of disease which might be amenable to study in future intervention trials. The authors agree that quantitative measures of ataxia are desirable as biomarkers. Methods are discussed that allow quantification of ataxia in laboratory as well as in clinical and real-life settings, for instance at the patients' home. Future studies are needed to demonstrate their usefulness as biomarkers in pharmaceutical or rehabilitation trials.

Consensus paper: management of degenerative cerebellar disorders.

Treatment of motor symptoms of degenerative cerebellar ataxia remains difficult. Yet there are recent developments that are likely to lead to significant improvements in the future. Most desirable would be a causative treatment of the underlying cerebellar disease. This is currently available only for a very small subset of cerebellar ataxias with known metabolic dysfunction. However, increasing knowledge of the pathophysiology of hereditary ataxia should lead to an increasing number of medically sensible drug trials. In this paper, data from recent drug trials in patients with recessive and dominant cerebellar ataxias will be summarized. There is consensus that up to date, no medication has been proven effective. Aminopyridines and acetazolamide are the only exception, which are beneficial in patients with episodic ataxia type 2. Aminopyridines are also effective in a subset of patients presenting with downbeat nystagmus. As such, all authors agreed that the mainstays of treatment of degenerative cerebellar ataxia are currently physiotherapy, occupational therapy, and speech therapy. For many years, well-controlled rehabilitation studies in patients with cerebellar ataxia were lacking. Data of recently published studies show that coordinative training improves motor function in both adult and juvenile patients with cerebellar degeneration. Given the well-known contribution of the cerebellum to motor learning, possible mechanisms underlying improvement will be outlined. There is consensus that evidence-based guidelines for the physiotherapy of degenerative cerebellar ataxia need to be developed. Future developments in physiotherapeutical interventions will be discussed including application of non-invasive brain stimulation.

Intensive coordinative training improves motor performance in degenerative cerebellar disease.

OBJECTIVES: The cerebellum is known to play a strong functional role in both motor control and motor learning. Hence, the benefit of physiotherapeutic training remains controversial for patients with cerebellar degeneration. In this study, we examined the effectiveness of a 4-week intensive coordinative training for 16 patients with progressive ataxia due to cerebellar degeneration (n = 10) or degeneration of afferent pathways (n = 6). METHODS: Effects were assessed by clinical ataxia rating scales, individual goal attainment scores, and quantitative movement analysis. Four assessments were performed: 8 weeks before, immediately before, directly after, and 8 weeks after training. To control for variability in disease progression, we used an intraindividual control design, where performance changes with and without training were compared. RESULTS: Significant improvements in motor performance and reduction of ataxia symptoms were observed in clinical scores after training and were sustained at follow-up assessment. Patients with predominant cerebellar ataxia revealed more distinct improvement than patients with afferent ataxia in several aspects of gait like velocity, lateral sway, and intralimb coordination. Consistently, in patients with cerebellar but without afferent ataxia, the regulation of balance in static and dynamic balance tasks improved significantly. CONCLUSION: In patients with cerebellar ataxia, coordinative training improves motor performance and reduces ataxia symptoms, enabling them to achieve personally meaningful goals in everyday life. Training effects were more distinct for patients whose afferent pathways were not affected. For both groups, continuous training seems crucial for stabilizing improvements and should become standard of care. LEVEL OF EVIDENCE: This study provides Class III evidence that coordinative training improves motor performance and reduces ataxia symptoms in patients with progressive cerebellar ataxia.

Current advances in lesion-symptom mapping of the human cerebellum.

While high-resolution structural magnetic resonance imaging (MRI) combined with newer analysis methods has become a powerful tool in human cerebral lesion studies, comparatively few studies have used these advanced imaging techniques to study lesions of the human cerebellum and their associated symptoms. This review will summarize the methodology of MRI-based lesion-symptom mapping of the human cerebellum and discuss its potential for gaining insights into cerebellar function. The investigation of patients with defined focal lesions yields the greatest potential for obtaining meaningful correlations between lesion site and behavioral deficits. In smaller groups of patients overlay plots and subtraction analysis are good options. If larger groups of patients are available, different statistical techniques have been introduced to compare behavior and lesion site on a voxel-by-voxel basis. Although localization in degenerative cerebellar disorders is less accurate because of the diffuse nature of the disease, certain information about the supposed function of larger subdivisions of the cerebellum can be gained. Examples are given which show that lesion-symptom mapping allows to investigate the function of the intermediate zone and cerebellar nuclei. We conclude that meaningful correlations between lesion site and behavioral data can be obtained in patients with degenerative as well as focal cerebellar disorders.

The influence of focal cerebellar lesions on the control and adaptation of gait.

Cerebellar ataxic gait is influenced greatly by balance disorders, most likely caused by lesions of the medial zone of the cerebellum. The contributions of the intermediate and lateral zone to the control of limb dynamics for gait and the adaptation of locomotor patterns are less well understood. In this study, we analysed locomotion and goal-directed leg movements in 12 patients with chronic focal lesions after resection of benign cerebellar tumours. The extent of the cortical lesion and possible involvement of the cerebellar nuclei was determined by 3D-MR imaging. The subjects (age range 13-39 years, mean 20.3; seven female; ICARS score: mean 5.7, SD 6.3) performed three tasks: goal-directed leg placement, walking and walking with additional weights on the shanks. Based on the performance on the first two tasks, patients were categorized as impaired or unimpaired for leg placement and for dynamic balance control in gait. The subgroup with impaired leg placement but not the subgroup with impaired balance showed abnormalities in the adaptation of locomotion to additional loads. A detailed analysis revealed specific abnormalities in the temporal aspects of intra-limb coordination for leg placement and adaptive locomotion. These findings indicate that common neural substrates could be responsible for intra-limb coordination in both tasks. Lesion-based MRI subtraction analysis revealed that the interposed and the adjacent dentate nuclei were more frequently affected in patients with impaired compared to unimpaired leg placement, whereas the fastigial nuclei (and to a lesser degree the interposed nuclei) were more frequently affected in patients with impaired compared with unimpaired dynamic balance control. The intermediate zone appears thus to be of particular importance for multi-joint limb control in both goal-directed leg movements and in locomotion. For locomotion, our results indicate an influence of the intermediate zone on dynamic balance control as well as on the adaptation to changes in limb dynamics.

Lesion-symptom mapping of the human cerebellum.

High-resolution structural magnetic resonance imaging (MRI) has become a powerful tool in human cerebellar lesion studies. Structural MRI is helpful to analyse the localisation and extent of cerebellar lesions and to determine possible extracerebellar involvement. Functionally meaningful correlations between a cerebellar lesion site and behavioural data can be obtained both in subjects with degenerative as well as focal cerebellar disorders. In this review, examples are presented which demonstrate that MRI-based lesion-symptom mapping is helpful to study the function of cerebellar cortex and cerebellar nuclei. Behavioural measures were used which represent two main areas of cerebellar function, that is, motor coordination and motor learning. One example are correlations with clinical data which are in good accordance with the known functional compartmentalisation of the cerebellum in three sagittal zones: In patients with cerebellar cortical degeneration ataxia of stance and gait was correlated with atrophy of the medial (and intermediate) cerebellum, oculomotor disorders with the medial, dysarthria with the intermediate and limb ataxia with atrophy of the intermediate and lateral cerebellum. Similar findings were obtained in patients with focal lesions. In addition, in patients with acute focal lesions, a somatotopy in the superior cerebellar cortex was found which is in close relationship to animal data and functional MRI data in healthy control subjects. Finally, comparison of data in patients with acute and chronic focal lesions revealed that lesion site appears to be critical for motor recovery. Recovery after lesions to the nuclei of the cerebellum was less complete. Another example which extended knowledge about functional localisation within the cerebellum is classical conditioning of the eyeblink response, a simple form of motor learning. In healthy subjects, learning rate was related to the volume of the cortex of the posterior cerebellar lobe. In patients with focal cerebellar lesions, acquisition of eyeblink conditioning was significantly reduced in lesions including the cortex of the superior posterior lobe, but not the inferior posterior lobe. Disordered timing of conditioned eyeblink responses correlated with lesions of the anterior lobe. Findings are in good agreement with the animal literature. Different parts of the cerebellar cortex may be involved in acquisition and timing of conditioned eyeblink responses in humans. These examples demonstrate that MRI-based lesion-symptom mapping is helpful to study the contribution of functionally relevant cerebellar compartments in motor control and recovery in patients with cerebellar disease. In addition, information about the function of cerebellar cortex and nuclei can be gained.

A controlled study of the effects of alendronate in a growing mouse model of osteogenesis imperfecta.

Recent studies have reported that bisphosphonates reduce fracture incidence and improve bone density in children with osteogenesis imperfecta (OI). However, questions still persist concerning the effect of these drugs on bone properties such as ultrastructure and quality, particularly in the growing patient. To address these issues, the third-generation bisphosphonate alendronate was evaluated in the growing oim/oim mouse, an animal model of moderate-to-severe OI. Alendronate was administered to 6-week-old mice during a period of active growth at a dosage of 73 microg alendronate/kg/day for the first 4 weeks and 26 microg alendronate/kg/day for the next 4 weeks. Positive treatment effects included a reduction in the number of fractures sustained by the alendronate-treated oim/oim mice compared with untreated oim/oim mice (2.1+/-2.0 vs 3.2+/-1.6 fractures per mouse), increased femoral metaphyseal density (0.111+/-0.02 vs 0.034+/-0.04 g/cm2), a tendency towards reduced tibial bowing (4.0+/-3.7 vs 6.1+/-5.8 degrees), and towards increased femoral diameter (1.22+/-0.12 vs 1.15+/-0.11 mm). Potential negative effects included a persistence of calcified cartilage in the treated oim/oim metaphyses compared with treated wildtype (+/+) (33.8+/-11.1 vs 22.1+/-10.2%), and significantly shorter femora compared with nontreated oim/oim mice (14.8+/-0.67 vs 15.3+/-0.37 mm). This preclinical study demonstrates that alendronate is effective in reducing fractures in a growing mouse model of OI, and is also an important indicator of potential positive and negative outcomes of third-generation bisphosphonate therapy in children with OI.

The material basis for reduced mechanical properties in oim mice bones.

Osteogenesis imperfecta (OI), a heritable disease caused by molecular defects in type I collagen, is characterized by skeletal deformities and brittle bones. The heterozygous and homozygous oim mice (oim/+ and oim/oim) exhibit mild and severe OI phenotypes, respectively, serving as controlled animal models of this disease. In the current study, bone geometry, mechanics, and material properties of 1-year-old mice were evaluated to determine factors that influence the severity of phenotype in OI. The oim/oim mice exhibited significantly smaller body size, femur length, and moment of area compared with oim/+ and wild-type (+/+) controls. The oim/oim femur mechanical properties of failure torque and stiffness were 40% and 30%, respectively, of the +/+ values, and 53% and 36% of the oim/+ values. Collagen content was reduced by 20% in the oim/oim compared with +/+ bone and tended to be intermediate to these values for the oim/+. Mineral content was not significantly different between the oim/oim and +/+ bones. However, the oim/oim ash content was significantly reduced compared with that of the oim/+. Mineral carbonate content was reduced by 23% in the oim/oim bone compared with controls. Mineral crystallinity was reduced in the oim/oim and oim/+ bone compared with controls. Overall, for the majority of parameters examined (geometrical, mechanical, and material), the oim/+ values were intermediate to those of the oim/oim and +/+, a finding that parallels the phenotypes of the mice. This provides evidence that specific material properties, such as mineral crystallinity and collagen content, are indicative and possibly predictive of bone fragility in this mouse model, and by analogy in human OI.

Repeated circadian growth hormone, luteinizing hormone, and follicle-stimulating hormone in children: influence of 9-alpha-fluorohydrocortisone.

Growth hormone (GH), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) in plasma of 5 children at different pubertal stages and suffering from moderate orthostatic complaints, were measured by radioimmunoassay (RIA). Parameters for secretory capacity were arginine loading and circadian hormonal patterns in hourly intervals from 8 a.m. to 8 p.m. and in half-hourly intervals from 8 p.m. to 8 a.m. before and after 6 weeks treatment with 9-alpha-fluorohydrocortisone (9-alpha-F, Astonin-H, Fa. Merck, Darmstadt, 0.1--0.2 mg/day. Plasma GH during arginine tests and in circadian levels remained unchanged, but circadian LH showed a consistent slight rise in all children. With pubertal development, magnitude and timing of GH peaks increased in boys, and rather decreased in the two girls toward late puberty. Episodic fluctuation of LH and FSH were more marked during sleep, and increased in the three bosy as puberty advanced. Similar intraindividual patterns for GH and LH, but not for FSH were noted in 4 children. Timing of GH and LH peaks appeared to be correlated. An intrinsic hereditary long-term regulatory principle is discussed.