Cerebellar transcranial direct current stimulation modulates the fMRI signal in the cerebellar nuclei in a simple motor task.

BACKGROUND: In a seminal paper, Galea et al. (Modulation of cerebellar excitability by polarity-specific noninvasive direct current stimulation. 2009. J Neurosci 29, 9115-9122) showed that cerebellar transcranial direct current stimulation (ctDCS) alters cerebellar-M1 connectivity. This effect has been explained by ctDCS-related changes of excitability of the cerebellar cortex with consecutive modulation of its main output, the dentate-thalamo-cortical pathway. OBJECTIVES: The aim of this functional magnetic resonance imaging (fMRI) study was to provide evidence that cathodal ctDCS decreases the activity of the cerebellar cortex, resulting in increased activity of the cerebellar nuclei, whereas anodal ctDCS has the opposite effect. METHODS: A total of 48 participants (female/male: 23/25, age: 23.8 ±â€¯4.1yrs., mean ±â€¯standard deviation) performed a finger tapping task with the right hand in a 3T MRI scanner. Functional MR images were acquired prior, during and after tDCS of the right cerebellum. Participants were assigned randomly to anodal, cathodal or sham ctDCS. RESULTS: No significant difference of cerebellar cortical activation was found after comparing the three modes of stimulation. On the level of the dentate nuclei, however, a significant increase of activation was detected during and after cathodal stimulation. Furthermore, dentate nuclei activation was suppressed on a trend level following anodal stimulation. CONCLUSIONS: The present findings support the hypothesis that cathodal ctDCS leads to a disinhibition of the dentate nucleus, whereas anodal ctDCS may have the opposite effect.

Effects of transcranial direct current stimulation on grip force control in patients with cerebellar degeneration.

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.

Cerebellar patients do not benefit from cerebellar or M1 transcranial direct current stimulation during force-field reaching adaptation.

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.NEW & NOTEWORTHY 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.

Activation of the cerebellar cortex and the dentate nucleus in a prism adaptation fMRI study.

During prism adaptation two types of learning processes can be distinguished. First, fast strategic motor control responses are predominant in the early course of prism adaptation to achieve rapid error correction within few trials. Second, slower spatial realignment occurs among the misaligned visual and proprioceptive sensorimotor coordinate system. The aim of the present ultra-highfield (7T) functional magnetic resonance imaging (fMRI) study was to explore cerebellar cortical and dentate nucleus activation during the course of prism adaptation in relation to a similar visuomotor task without prism exposure. Nineteen young healthy participants were included into the study. Recently developed normalization procedures were applied for the cerebellar cortex and the dentate nucleus. By means of subtraction analysis (early prism adaptation > visuomotor, early prism adaptation > late prism adaptation) we identified ipsilateral activation associated with strategic motor control responses within the posterior cerebellar cortex (lobules VIII and IX) and the ventro-caudal dentate nucleus. During the late phase of adaptation we observed pronounced activation of posterior parts of lobule VI, although subtraction analyses (late prism adaptation > visuomotor) remained negative. These results are in good accordance with the concept of a representation of non-motor functions, here strategic control, within the ventro-caudal dentate nucleus.

Consensus paper: Language and the cerebellum: an ongoing enigma.

In less than three decades, the concept "cerebellar neurocognition" has evolved from a mere afterthought to an entirely new and multifaceted area of neuroscientific research. A close interplay between three main strands of contemporary neuroscience induced a substantial modification of the traditional view of the cerebellum as a mere coordinator of autonomic and somatic motor functions. Indeed, the wealth of current evidence derived from detailed neuroanatomical investigations, functional neuroimaging studies with healthy subjects and patients and in-depth neuropsychological assessment of patients with cerebellar disorders shows that the cerebellum has a cardinal role to play in affective regulation, cognitive processing, and linguistic function. Although considerable progress has been made in models of cerebellar function, controversy remains regarding the exact role of the "linguistic cerebellum" in a broad variety of nonmotor language processes. This consensus paper brings together a range of different viewpoints and opinions regarding the contribution of the cerebellum to language function. Recent developments and insights in the nonmotor modulatory role of the cerebellum in language and some related disorders will be discussed. The role of the cerebellum in speech and language perception, in motor speech planning including apraxia of speech, in verbal working memory, in phonological and semantic verbal fluency, in syntax processing, in the dynamics of language production, in reading and in writing will be addressed. In addition, the functional topography of the linguistic cerebellum and the contribution of the deep nuclei to linguistic function will be briefly discussed. As such, a framework for debate and discussion will be offered in this consensus paper.

Prevalence of right-to-left shunts on transcranial Doppler in chronic migraine and medication-overuse headache.

BACKGROUND: It was suggested that right-to-left shunt (RLS) may be highly prevalent in chronic migraine (CM) patients, indicating that patent foramen ovale (PFO) might be an aggravating and chronifying factor of migraine. Since a high proportion of chronic migraineurs also have medication-overuse headache (MOH), one may wonder if they have a more severe form of the disorder and more frequently a PFO. OBJECTIVE: The objective of this study is to determine the prevalence and grade of RLS in patients suffering from CM and MOH. METHODS: A cross-sectional multicenter study of air-contrast transcranial Doppler was conducted in 159 patients with CM ( N = 57) or MOH ( N = 102) attending a tertiary headache clinic. RESULTS: The prevalence of RLS in CM was 37% (11% large shunts) and in MOH patients 31% (13% large shunts). There was no difference between the two groups ( P = 0.49). CONCLUSION: RLS prevalence in CM is within the upper range of those reported in episodic migraine without aura or in the general population, and not higher in MOH. PFO is thus unlikely to have a significant causal role in these chronic headaches.

No evidence of jugular venous valve insufficiency in patients with migraine--a controlled study.

BACKGROUND: Migraine with aura is associated with patent foramen ovale and right-left-shunt. Jugular venous valve insufficiency is a further vascular anomaly. It is a frequent finding in transient global amnesia which is associated with migraine. Therefore, we investigated the prevalence of jugular venous valve insufficiency in migraine. METHODS: Subjects included in this study were participants of the population based German Headache Study on the prevalence of primary headaches. In 36 patients with migraine with aura, 50 patients with migraine without aura and 43 controls without headaches duration of backward venous flow, peak velocity flow and diameters of the jugular venous valves were assessed by color-coded duplex and Doppler sonography and compared between groups. In all migraine patients, examination was performed between and not during migraine attacks. Therefore, 9 additional patients with chronic daily headache were investigated during headache. RESULTS: We did not find statistically significant differences in duration of flow, peak velocity flow and diameter of the jugular venous valves in patients with migraine with aura (mean values 0.53 ± 0.43 sec; 35.47 ± 33.87 cm/sec; 8.84 ± 3.17 mm), migraine without aura (0.61 ± 0.63 sec; 33.39 ± 25.80 cm/sec; 8.15 ± 3.02 mm) or controls (0.64 ± 0.51 sec; 35.28 ± 31.76 cm/sec; 8.79 ± 2.97 mm) (group effects p-values >0.41). For all parameters results were the same for the left and the right side of jugular venae (side effects p-values >0.09). Also patients with chronic daily migraine with headache during the examination showed no differences to controls (0.52 ± 0.49 sec; 27.95 ± 21,75 cm/sec; 8.07 ± 2.71 mm) (all p-values > 0.23). CONCLUSIONS: The prevalence of internal jugular venous valve insufficiency is not increased in persons with migraine.

Cerebellar mutism.

Cerebellar mutism occurs in about 25% of children following posterior fossa tumor surgery. It is usually accompanied by other neurological and behavioral disturbances. Mutism is transient in nature lasting several days to months and is frequently followed by dysarthria. In addition, impairment of language and other neuropsychological functions can be found after long term follow up in the majority of patients. The pathophysiological background of mutism may be higher speech dysfunction mediated by crossed cerebello-cerebral diaschisis which is frequently found during the mute period. Foremost injury to the bilateral dentatothalamocortical tract appears to be critical for the development of cerebello-cerebral diaschisis and subsequent mutism. Direct cerebellar injury is the likely reason for persisting deficits after the mute period. Minimization of injury to the dentatothalamocortical tract during surgery may be promising in the prevention of mutism. While there is no established treatment of mutism, early speech and rehabilitation therapy is recommended.

Prevalence of cardiac right left shunts in migraine: a population-based case-control study.

We aimed to investigate the prevalence of cardiac right left shunts (RLS) in population-based samples of subjects with migraine with aura (n = 42), migraine without aura (n = 44) and controls without headache (n = 41). Cardiac RLS was assessed with transcranial Doppler sonography with intravenous injection of saline. Prevalence of RLS was highest in migraineurs with aura (45.2%) compared to migraineurs without aura (34.1%) and controls (41.5%). Permanent as opposed to latent RLS was more common among patients with migraine with aura (40.5%) than in patients with migraine without aura (23.3%) or controls (24.4%). Differences did not reach statistical significance between the three groups (p = 0.564 for RLS prevalence, p = 0.349 for prevalence of permanent shunts). Our data implicate a trend towards higher prevalence of RLS with larger shunts in subjects with migraine with aura.

Deficient use of visual information in estimating hand position in cerebellar patients.

We tested cerebellar degeneration in human patients in a task designed to isolate different aspects of motor planning and found a specific relationship between their ability to do inverse kinematic transformation and sparing of Crus I. Our approach was based on an experimental design introduced by Sober and Sabes (2003, 2005). Their paradigm allows behavioral deficits in planning of movement direction to be dissociated from deficits in generation of motor commands and also allows for the relative role played by visual and proprioceptive information to be quantified. Perturbation of visual information about hand position affected cerebellar degeneration patients (N = 12) and age-matched controls equally in determining movement direction, but had less of an effect in both groups in the transformation of movement direction to motor command. However, when provided with vision of the joints, control participants were more affected in generating the motor command in perturbed trials, and cerebellar degeneration participants were not. Thus, cerebellar patients were less able to use visual information about the joints in generating motor commands. Voxel-based morphometric analysis showed that this inability was primarily correlated with degeneration of Crus I. These results show that the cerebellum plays a role in motor planning, and specifically in the generation of inverse kinematic models for sensorimotor processing. The involvement of Crus I is consistent with an emerging picture in which increasingly posterior lobules of the anterior cerebellar cortex are associated with increasingly complex and abstract aspects of motor behavior.

Evidence for a motor somatotopy in the cerebellar dentate nucleus--an FMRI study in humans.

Previous anatomical studies in monkeys have shown that forelimb motor representation is located caudal to hindlimb representation within the dorso-rostral dentate nucleus. Here we investigate human dentate nucleus motor somatotopy by means of ultra-highfield (7 T) functional magnetic brain imaging (fMRI). Twenty five young healthy males participated in the study. Simple finger and foot movement tasks were performed to identify dentate nucleus motor areas. Recently developed normalization procedures for group analyses were used for the cerebellar cortex and the cerebellar dentate nucleus. Cortical activations were in good accordance with the known somatotopy of the human cerebellar cortex. Dentate nucleus activations following motor tasks were found in particular in the ipsilateral dorso-rostral nucleus. Activations were also present in other parts of the nucleus including the contralateral side, and there was some overlap between the body part representations. Within the ipsilateral dorso-rostral dentate, finger activations were located caudally compared to foot movement-related activations in fMRI group analysis. Likewise, the centre of gravity (COG) for the finger activation was more caudal than the COG of the foot activation across participants. A multivariate analysis of variance (MANOVA) on the x, y, and z coordinates of the COG indicated that this difference was significant (P = 0.043). These results indicate that in humans, the lower and upper limbs are arranged rostro-caudally in the dorsal aspect of the dentate nucleus, which is consistent with studies in non-human primates.

Structural and functional magnetic resonance imaging of the human cerebellar nuclei.

The present review focuses on recent developments in structural and functional magnetic resonance imaging (MRI) of the deep cerebellar nuclei (DCN), the main output structure of the cerebellum. The high iron content in the DCN allows for their visibility in T2*-weighted images. Spatial resolution has improved allowing the identification of DCN in individual cerebellar patients and healthy subjects. Based on findings in larger groups of healthy subjects, probabilistic MRI-based atlases of the deep cerebellar nuclei have been developed, which are important tools in human lesion and functional imaging studies. High iron content in the DCN, on the other hand, decreases the blood oxygenation level dependent-signal making functional imaging a difficult challenge. Compared to the vast amount of studies reporting activation of the cerebellar cortex, the number of studies demonstrating activation of the DCN is much less. Most studies report activation of the dentate nucleus. Dentate activations appear to be more reliable in more complex tasks for reasons currently unknown. As yet, few studies tried to show activations of functional subunits of the dentate nucleus. Increased signal-to-noise ratio and better spatial resolution using higher MR field strength together with recent progress in dentate normalization methods will allow identification of functional subunits and their interactions with the cerebellar cortex in future studies.

Impaired prehension is associated with lesions of the superior and inferior hand representation within the human cerebellum.

Impairment of patients with cerebellar disease in prehension is well recognized. So far specific localizations within the human cerebellum associated with the impairment have rarely been assessed. To address this question we performed voxel-based lesion symptom mapping (VLSM) in patients with chronic focal cerebellar lesions in relation to specific deficits in prehensile movements. Patients with stroke within the posterior inferior cerebellar artery territory (n = 13) or the superior cerebellar artery (SCA) territory (n = 7) and corresponding control subjects were included in the study. Participants reached out, grasped, and lifted an object with either the left or right hand and with fast or normal movement speed. Both kinematic and grip-force parameters were recorded. Magnetic resonance imaging anatomical scans of the cerebellum were acquired, and lesions were marked as regions of interest. For VLSM analysis, a nonparametric test (Brunner-Munzel) was applied. Cerebellar patients showed clear abnormalities in hand transport (impaired movement speed and straightness) and, to a lesser degree, in hand shaping (increased finger touch latencies) while grip function was preserved. Deficits were most prominent in patients with SCA lesions and for ipsilesional, fast movements. Disorders in hand transport may be more difficult to compensate than deficits in hand shaping and grip-force control in chronic focal lesions of the cerebellum because of higher demands on predictive control of interaction torques. Lesions of the superior cerebellar cortex (lobules IV, V, VI) were associated with slower hand transport, whereas lesions of both superior (lobules VI, V, VI) and inferior cerebellar cortex (lobules VII, VIII) were associated with impaired movement straightness. These findings show that both the superior and inferior hand representations within the cerebellum contribute to hand transport during prehensile movements; however, they may have a different functional role.

Structural gray and white matter changes in patients with HIV.

In this cross-sectional study we used magnetic resonance imaging (MRI)-based voxel based morphometry (VBM) in a sample of HIV positive patients to detect structural gray and white matter changes. Forty-eight HIV positive subjects with (n = 28) or without (n = 20) cognitive deficits (mean age 48.5 ± 9.6 years) and 48 age- and sex-matched HIV negative controls underwent MRI for VBM analyses. Clinical testing in HIV patients included the HIV dementia scale (HDS), Unified Parkinson's Disease Rating Scale (UPDRS) and the grooved pegboard test. Comparing controls with HIV positive patients with cognitive dysfunction (n = 28) VBM showed gray matter decrease in the anterior cingulate and temporal cortices along with white matter reduction in the midbrain region. These changes were more prominent with increasing cognitive decline, when assigning HIV patients to three cognitive groups (not impaired, mildly impaired, overtly impaired) based on performance in the HIV dementia scale. Regression analysis including all HIV positive patients with available data revealed that prefrontal gray matter atrophy in HIV was associated with longer disease duration (n = 48), while motor dysfunction (n = 48) was associated with basal ganglia gray matter atrophy. Lower CD4 cell count (n = 47) correlated with decrease of occipital gray matter. Our results provide evidence for atrophy of nigro-striatal and fronto-striatal circuits in HIV. This pattern of atrophy is consistent with motor dysfunction and dysexecutive syndrome found in HIV patients with HIV-associated neurocognitive disorder.

Single nucleotide polymorphisms of the serotonin transporter gene in migraine--an association study.

We report a case-control study with 251 unrelated migraine patients and 192 unrelated healthy controls to evaluate an association between the polymorphisms of the 5-HT transporter (5-HTT) gene rs2066713 and rs1979572 and different migraine phenotypes. We found a genetic association for the A allele of rs1979572 for migraine with aura (MA) especially in women as well as a significant lower prevalence for MA for carrier of the A allele of rs2066713 in women. These findings support previous results suggesting that the 5-HTT gene is involved in the polygenic etiology of MA. These data further suggest that women are more likely to be clinically affected by mutations in the 5-HTT gene than men.