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Neurodegeneration of the cerebellum progresses over years and primarily affects cerebellar cortex. It leads to a progressive loss of control and coordination of gait, posture, speech, fine motor, and oculomotor function. Yet, little is known how the cerebro-cerebellar network compensates for the loss in cerebellar cortical neurons. To address this knowledge gap, we examined 30 people with cerebellar cortical degeneration and a group of 30 healthy controls. We assessed visuomotor performance during a forearm-pointing task to 10°, 25°, and 50° targets. In addition, using MRI imaging, we determined neurodegenerative-induced changes in gray matter volume (GMV) in the cerebro-cerebellar network and correlated them to markers of motor performance. The main results are as follows: first, the relative joint position error (RJPE) during pointing was significantly greater in the ataxia group for all targets confirming the expected motor control deficit. Second, in the ataxia group, GMV was significantly reduced in cerebellar cortex but increased in the deep cerebellar nuclei. Motor error (RJPE) correlated negatively with decreased cerebellar GMV but positively with increased GMV in supplementary motor area (SMA) and premotor cortex. GMV of the deep cerebellar nuclei did not correlate significantly with markers of motor performance. We discuss whether the GMV changes in the cerebellar output nuclei and the extracerebellar efferent targets in secondary motor cortex can be understood as a central compensatory response to the neurodegeneration of the cerebellar cortex. NEW & NOTEWORTHY Neurodegeneration of the cerebellum progresses over years and primarily affects cerebellar cortex. It leads to a progressive loss of control and coordination of movement. We here show that the neurodegenerative process not only leads to cells loss in cerebellar cortex but also induces neurostructural changes in the form of increased gray matter in the efferent targets of the cerebellar cortex, namely, the cerebellar output nuclei, the SMA, and premotor cortex.

Classical delay eyeblink conditioning is likely the most commonly used paradigm to study cerebellar learning. As yet, few studies have focused on extinction and savings of conditioned eyeblink responses (CRs). Saving effects, which are reflected in a reacquisition after extinction that is faster than the initial acquisition, suggest that learned associations are at least partly preserved during extinction. In this study, we tested the hypothesis that acquisition-related plasticity is nihilated during extinction in the cerebellar cortex, but retained in the cerebellar nuclei, allowing for faster reacquisition. Changes of 7 T functional magnetic resonance imaging (fMRI) signals were investigated in the cerebellar cortex and nuclei of young and healthy human subjects. Main effects of acquisition, extinction, and reacquisition against rest were calculated in conditioned stimulus-only trials. First-level β values were determined for a spherical region of interest (ROI) around the acquisition peak voxel in lobule VI, and dentate and interposed nuclei ipsilateral to the unconditioned stimulus. In the cerebellar cortex and nuclei, fMRI signals were significantly lower in extinction compared to acquisition and reacquisition, but not significantly different between acquisition and reacquisition. These findings are consistent with the theory of bidirectional learning in both the cerebellar cortex and nuclei. It cannot explain, however, why conditioned responses reappear almost immediately in reacquisition following extinction. Although the present data do not exclude that part of the initial memory remains in the cerebellum in extinction, future studies should also explore changes in extracerebellar regions as a potential substrate of saving effects. Hum Brain Mapp 38:3957-3974, 2017. © 2017 Wiley Periodicals, Inc., (© 2017 Wiley Periodicals, Inc.)

Spinocerebellar ataxia type 3, spinocerebellar ataxia type 6 and Friedreich's ataxia are common hereditary ataxias. Different patterns of atrophy of the cerebellar cortex are well known. Data on cerebellar nuclei are sparse. Whereas cerebellar nuclei have long been thought to be preserved in spinocerebellar ataxia type 6, histology shows marked atrophy of the nuclei in Friedreich's ataxia and spinocerebellar ataxia type 3. In the present study susceptibility weighted imaging was used to assess atrophy of the cerebellar nuclei in patients with spinocerebellar ataxia type 6 (n = 12, age range 41-76 years, five female), Friedreich's ataxia (n = 12, age range 21-55 years, seven female), spinocerebellar ataxia type 3 (n = 10, age range 34-67 years, three female), and age- and gender-matched controls (total n = 23, age range 22-75 years, 10 female). T1-weighted magnetic resonance images were used to calculate the volume of the cerebellum. In addition, ultra-high field functional magnetic resonance imaging was performed with optimized normalization methods to assess function of the cerebellar cortex and nuclei during simple hand movements. As expected, the volume of the cerebellum was markedly reduced in spinocerebellar ataxia type 6, preserved in Friedreich's ataxia, and mildy reduced in spinocerebellar ataxia type 3. The volume of the cerebellar nuclei was reduced in the three patient groups compared to matched controls (P-values < 0.05; two-sample t-tests). Atrophy of the cerebellar nuclei was most pronounced in spinocerebellar ataxia type 6. On a functional level, hand-movement-related cerebellar activation was altered in all three disorders. Within the cerebellar cortex, functional magnetic resonance imaging signal was significantly reduced in spinocerebellar ataxia type 6 and Friedreich's ataxia compared to matched controls (P-values < 0.001, bootstrap-corrected cluster-size threshold; two-sample t-tests). The difference missed significance in spinocerebellar ataxia type 3. Within the cerebellar nuclei, reductions were significant when comparing spinocerebellar ataxia type 6 and Friedreich's ataxia to matched controls (P < 0.01, bootstrap-corrected cluster-size threshold; two-sample t-tests). Susceptibility weighted imaging allowed depiction of atrophy of the cerebellar nuclei in patients with Friedreich's ataxia and spinocerebellar ataxia type 3. In spinocerebellar ataxia type 6, pathology was not restricted to the cerebellar cortex but also involved the cerebellar nuclei. Functional magnetic resonance imaging data, on the other hand, revealed that pathology in Friedreich's ataxia and spinocerebellar ataxia type 3 is not restricted to the cerebellar nuclei. There was functional involvement of the cerebellar cortex despite no or little structural changes., (© The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

There are controversies whether learning of conditioned eyeblink responses primarily takes place within the cerebellar cortex, the interposed nuclei, or both. It has also been suggested that the cerebellar cortex may be important during early stages of learning, and that there is a shift to the cerebellar nuclei during later stages. As yet, human studies have provided little to resolve this question. In the present study, we established a setup that allows ultra-high-field 7T functional magnetic resonance imaging (fMRI) of the cerebellar cortex and interposed cerebellar nuclei simultaneously during delay eyeblink conditioning in humans. Event-related fMRI signals increased concomitantly in the cerebellar cortex and nuclei during early acquisition of conditioned eyeblink responses in 20 healthy human subjects. ANOVAs with repeated-measures showed significant effects of time across five blocks of 20 conditioning trials in the cortex and nuclei (p < 0.05, permutation corrected). Activations were most pronounced in, but not limited to, lobules VI and interposed nuclei. Increased activations were most prominent at the first time the maximum number of conditioned responses was achieved. Our data are consistent with a simultaneous and synergistic two-site model of learning during acquisition of classically conditioned eyeblinks. Because increased MRI signal reflects synaptic activity, concomitantly increased signals in the cerebellar nuclei and cortex are consistent with findings of learning related potentiation at the mossy fiber to nuclear cell synapse and mossy fiber to granule cell synapse. Activity related to the expression of conditioned responses, however, cannot be excluded., (Copyright © 2015 the authors 0270-6474/15/351228-12$15.00/0.)

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., (Copyright © 2013 Wiley Periodicals, Inc.)

We investigated whether higher activation of the cerebellar cortex in unpredictable compared to predictable sequential finger movements reflects higher demands in motor response selection or also increases in demands on motor sequencing. Furthermore, we asked the question whether the cerebellar nuclei show a similar or reversed response profile as the cerebellar cortex. Ultra-high-field 7T functional magnetic resonance imaging was performed in nineteen right-handed, healthy young participants. Tasks involved finger tapping of a constant sequence, a random sequence, and with one finger at a time (no sequence). Conditions involved the same number of movements of fingers II-V. The three tasks were accompanied by the activation of the known hand areas within the cerebellar cortex and dentate nuclei. Activation of the cerebellar cortex and the dorsorostral dentate was significantly increased in the random-sequence condition compared to both the constant-sequence and the no-sequence conditions, with no significant difference between the constant-sequence and the no-sequence conditions. Error rate and movement frequency was not significantly different between conditions. Thus, differences between conditions cannot be explained by differences in motor execution. Because no difference was observed between the no-sequence and the constant-sequence conditions, increased cerebellar activation in the random-sequence condition likely reflects increased demands in motor response selection. Co-activation of cerebellar cortex and nuclei may be a consequence of excitatory afferent collaterals to the nuclei, "rebound-firing" of dentate neurons, and/or inhibitory synaptic input from Purkinje cells.

The first aim of the present study was to extend previous findings of similar cerebellar cortical areas being involved in verbal and spatial n-back working memory to the level of the cerebellar nuclei. The second aim was to investigate whether different areas of the cerebellar cortex and nuclei contribute to different working memory tasks (n-back vs. Sternberg tasks). Young and healthy subjects participated in two functional magnetic resonance imaging (fMRI) studies using a 7 T MR scanner with its increased signal-to-noise ratio. One group of subjects (n=21) performed an abstract and a verbal version of an n-back task contrasting a 2-back and 0-back condition. Another group of subjects (n=23) performed an abstract and a verbal version of a Sternberg task contrasting a high load and a low load condition. A block design was used. For image processing of the dentate nuclei, a recently developed region of interest (ROI) driven normalization method of the dentate nuclei was applied (Diedrichsen et al., 2011). Whereas activated areas of the cerebellar cortex and dentate nuclei were not significantly different comparing the abstract and verbal versions of the n-back task, activation in the abstract and verbal Sternberg tasks was significantly different. In both n-back tasks activation was most prominent at the border of lobules VI and Crus I, within lobule VII, and within the more caudal parts of the dentate nucleus bilaterally. In Sternberg tasks the most prominent activations were found in lobule VI extending into Crus I on the right. In the verbal Sternberg task activation was significantly larger within right lobule VI compared to the abstract Sternberg task and compared to the verbal n-back task. Activations of rostral parts of the dentate were most prominent in the verbal Sternberg task, whereas activation of caudal parts predominated in the abstract Sternberg task. On the one hand, the lack of difference between abstract and verbal n-back tasks and the lack of significant lateralization suggest a more general contribution of the cerebellum to working memory regardless of the modality. On the other hand, the focus of activation in right lobule VI in the verbal Sternberg task suggests specific cerebellar contributions to verbal working memory. The verbal Sternberg task emphasizes maintenance of stimuli via phonological rehearsal, whereas central executive demands prevail in n-back tasks. Based on the model of working memory by Baddeley and Hitch (1974), the present results show that different regions of the cerebellum support functions of the central executive system and one of the subsidiary systems, the phonological loop., (Copyright © 2012 Elsevier Inc. All rights reserved.)

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.

The acquisition and timing of delay-conditioned eyeblink responses (CRs) have been shown to be significantly impaired in patients with disorders restricted to the cortex of the superior cerebellum. We were interested if patients improve incidences and timing of CRs across three sessions on three consecutive days. A standard delay paradigm was used in 9 patients with diffuse cerebellar degeneration, 13 patients with ischemic cortical cerebellar lesions and in 13 controls. High-resolution magnetic resonance imaging (MR imaging) was used to ensure that hemispheral lobules VI and/ or Crus I were lesioned in all stroke patients with the interposed nuclei being preserved. On day 1 patients with stroke but not with degenerative disorders showed significant CR acquisition, although total CR incidences remained significantly lower than in controls. No further improvement was visible on days 2 and 3 neither in patients with focal lesions nor in patients with cerebellar degeneration. CRs occurred earlier in cerebellar patients, most pronounced in patients with degenerative disorders. In patients with stroke but not in the degenerative group timing had improved on the third day close to values of the control subjects. Findings show that lesions of the cerebellar cortex produce permanent deficits in the acquisition of delay-conditioned eyeblink responses. Overall, mean CR incidence was higher in focal compared to degenerative disorders, most likely because the critical lobules (VI and Crus I) were lesioned only in part. Intact anterior lobe, which it thought to contribute to CR timing, may explain recovery of disordered timing in focal cerebellar patients., (Copyright 2010 Elsevier B.V. All rights reserved.)

In the present study, acquisition and timing of conditioned eyeblink responses (CRs) were correlated with magnetic resonance imaging (MRI)-based cerebellar volume both in healthy human subjects and patients with cerebellar disease. Thirty-three healthy subjects and 25 patients with pure cortical cerebellar degeneration participated. Cerebellar volumes were measured for the cortex of the anterior lobe, the cortex of the posterior lobe, the white matter of the cerebellum and the cerebrum based on 3D MR images. CR parameters were assessed in a standard delay paradigm. In healthy subjects CR acquisition was significantly related to the volume of the grey matter of the posterior lobe, but neither to the volume of the grey matter of the anterior lobe, nor to the cerebellar white matter and nor to the cerebral volume. As expected, CR acquisition and volume of the cortex of the posterior lobe showed age-related decline in the controls. Furthermore, CR acquisition was significantly reduced in patients with cerebellar degeneration compared to controls. In the cerebellar group, however, no significant correlations between CR acquisition and any of the cerebellar volumes were observed. Floor effects are most likely responsible for this observation. Although CRs occurred significantly earlier in cerebellar patients compared to controls, no significant correlations between CR timing parameters and any of the cerebellar volumes were observed. Extending previous findings in healthy human subjects, age-related decline of the cerebellar cortex of the posterior lobe was related with a reduction of CR acquisition. Findings provide further evidence that the cerebellar cortex plays an important role in the acquisition of eyeblink conditioning in humans.

The aim of the present study was to examine somatotopy in the cerebellar cortex and a possible differential role of the cerebellar cortex and nuclei in functional outcome. Clinical findings and 3D MRI-based cerebellar lesions site were compared in a group of 90 patients with focal cerebellar lesion using International Cooperative Ataxia Rating Scale (ICARS) and voxel-based lesion-symptom mapping (VLSM). Separate analysis was performed in patients with acute and chronic ischemic lesions (n=43) and patients with acute and chronic surgical lesions (n=47). Thirty-eight patients were included after resection of a cerebellar tumor in childhood or adolescence. The most significant lesion symptom correlations were observed in the subgroup with acute ischemic lesions. Limb ataxia was significantly correlated with lesions of the interposed (NI) and part of the dentate nuclei (ND), ataxia of posture and gait with lesions of the fastigial nuclei (NF) including NI. Correlations with cortical lesions were less significant and present in the superior cerebellum only. Upper limb ataxia was correlated with lesions of vermal, paravermal and hemispheral lobules IV-V and VI, lower limb ataxia with lesions of vermal, paravermal and hemispheral lobules III and VI, dysarthria with lesions of paravermal and hemispheral lobules V and VI and ataxia of posture and gait with lesions of vermal and paravermal lobules II, III and IV. In the subgroups with chronic focal lesions, similar correlations were observed with lesions of the cerebellar nuclei, but significantly less correlations with lesions of the cerebellar cortex. Functional localization based on VLSM backs findings in previous animal and functional brain images studies in healthy human subjects. The lesion site appears to be critical for motor recovery. Lesions affecting the cerebellar nuclei are not fully compensated at any age and independent of the pathology in humans.

Blink reflex-related areas in the human cerebellum were studied using [15O]H2O PET in eight healthy subjects. Eyeblinks were evoked by airpuff stimulation and recorded via surface electrodes. PET analysis revealed a cerebellar increase of regional cerebral blood flow in vermal lobule VI and a small ipsilateral paravermal extension in the eyeblink condition compared to rest. This activation partly overlapped with areas found in recent fMRI and animal studies investigating the cerebellar involvement in control of the unconditioned and acquisition of the conditioned eyeblink response. In conclusion, vermal lobule VI extending to ipsilateral paravermal areas appears to be involved in control of the unconditioned eyeblink response.

The aim of the present study was to explore cerebellar contributions to the central executive in n-back working memory tasks using 7-T functional magnetic imaging (fMRI). We hypothesized that cerebellar activation increased with increasing working memory demands. Activations of the cerebellar cortex and dentate nuclei were compared between 0-back (serving as a motor control task), 1-back, and 2-back working memory tasks for both verbal and abstract modalities. A block design was used. Data of 27 participants (mean age 26.6 ± 3.8 years, female/male 12:15) were included in group statistical analysis. We observed that cerebellar cortical activations increased with higher central executive demands in n-back tasks independent of task modality. As confirmed by subtraction analyses, additional bilateral activations following higher executive demands were found primarily in four distinct cerebellar areas: (i) the border region of lobule VI and crus I, (ii) inferior parts of the lateral cerebellum (lobules crus II, VIIb, VIII, IX), (iii) posterior parts of the paravermal cerebellar cortex (lobules VI, crus I, crus II), and (iv) the inferior vermis (lobules VI, VIIb, VIII, IX). Dentate activations were observed for both verbal and abstract modalities. Task-related increases were less robust and detected for the verbal n-back tasks only. These results provide further evidence that the cerebellum participates in an amodal bilateral neuronal network representing the central executive during working memory n-back tasks. [ABSTRACT FROM AUTHOR]

To elucidate whether the cerebellar cortex may contribute to trace eyeblink conditioning in humans, eight patients with degenerative cerebellar disorders (four with sporadic adult onset ataxia, three with autosomal dominant cerebellar ataxia type III and one with spinocerebellar ataxia type 6) and eight age- and sex-matched healthy control subjects were investigated. Individual high resolution three-dimensional MRI data sets were acquired. As revealed by volumetric measurements of the cerebellum using ECCET software, patients showed cerebellar atrophy to various degrees. No abnormalities were observed in the control subjects. Eyeblink conditioning was performed twice using a tone of 40 ms as conditioned stimulus, followed by a short (400 ms) and a long (1,000 ms) trace interval and an air-puff of 100 ms as unconditioned stimulus. Using the short trace interval, eyeblink conditioning was significantly impaired in cerebellar patients compared to controls, even in those who fulfilled criteria of awareness. Using the long trace interval no significant group differences could be observed. The present findings of impaired trace eyeblink acquisition in patients with cortical cerebellar degeneration suggest that the cerebellar cortex in humans, in addition to the interposed nucleus, is involved in trace eyeblink conditioning, if the trace interval is relatively short. Using a long trace interval, the cerebellum appears to be less important. [ABSTRACT FROM AUTHOR]

More recent findings suggest a possible role of the cerebellum in nonmotor functions. Disability of individuals with cerebellar damage in rapidly shifting attention is one frequently used example to support cerebellar involvement in mental skills. The original proposal was based on findings in five children with chronic surgical lesions of the cerebellum and a young adult with a degenerative disorder. The aim of the present study was to repeat Akshoomoff and Courchesne's initial findings in a larger group of children with focal cerebellar lesions. Ten children with cerebellar lesions and 10 age- and sex-matched controls were tested. Neocerebellar areas were affected in all children with cerebellar damage except one based on detailed analysis of MRI scans. Subjects had to perform a focus and a shift attention task. Two visual and two auditory stimuli were presented in a pseudorandom order. An ellipse and a high-pitched tone were presented less frequently than a circle and a low-pitched tone. Rare stimuli were presented at five different time intervals. In the focus tasks, subjects had to react to the same rare stimulus of one of the two modalities. In the shift task, subjects had to switch between the two rare stimuli. Motor deficits based on reaction times were small in cerebellar children compared with controls. The ability of target detection did not significantly differ in the children with cerebellar lesions compared with the control children in both the focus and the shift attention task. In particular, children with cerebellar damage showed no significant impairment in rapid (<2 s) shifts of attention. The present findings indicate that the cerebellum may be less critical in attention related processes than suggested previously. [ABSTRACT FROM AUTHOR]

Cerebellar patients throw inaccurately in the left-right direction but the cause of this multijoint ataxia is unclear. We tested whether it was due, as originally proposed, to variable left-right directions of the hand path, or, alternatively, to variable timing of ball release occurring on a right to left curved hand path. We also examined the cause of the variability in hand path direction per se. Six right-handed cerebellar patients and six control subjects were instructed to throw tennis balls at a slow, medium and fast speed from a seated position while angular positions in 3D of five arm segments were recorded at 1000 Hz with the search-coil technique. Compared to controls, cerebellar patients threw slower and less accurately, had more variable timing of ball release occurring on a right to left curved hand path and had more variable left-right directions of hand paths at a fixed point in front of the sternum. In all cerebellar patients, ball left-right inaccuracy was related both to timing of ball release and to hand path direction at the fixed point. The cause of the increased variability in hand path direction varied between patients and could not be explained by disorder in a single joint rotation. No evidence was found that it resulted from variable stabilization at the shoulder during elbow extension. Instead, the more variable left-right direction of the hand path was related to the initial pattern of joint rotations occurring early in the throw before the onset of elbow extension, and to the amplitudes of radioulnar pronation and wrist abduction occurring late in the throw. The results emphasize that in the presence of a cerebellar lesion, ball left-right inaccuracy in overarm throws cannot be explained by a single disorder. Rather ball inaccuracy was likely due to disorders in central commands to proximal joint rotations that produced the hand path and in central commands to distal joints that controlled the timing of finger opening. [ABSTRACT FROM AUTHOR]

The role of the cerebellum in the classically conditioned, human lower-limb-withdrawal reflex was studied in ten patients with pure cerebellar diseases (CBL), ten patients showing additional extracerebellar symptoms (CBL+), and in 11 sex- and age-matched normal controls (CTRL). Where conditioning was successful, the electrically evoked, unconditioned response was preceded by a tone-conditioned response (CR). CR incidence was variable, with best results in the CTRL, significantly less in CBL, and lowest in CBL+. Although CRs could be established in subjects in all groups, a continuous increase in the CR incidence in the course of the recording session was observed primarily in CTRL. In CBL and CBL+, such a characteristic reflex acquisition was rather the exception. CR onsets in CBL were within the range of those in CTRL, but CR amplitude was significantly lower in CBL. Cerebellar patients with circumscribed lesions behaved differently in our motor-learning paradigm, depending on the lesion site. Patients suffering from pathology of the posterior inferior cerebellum showed a mean CR incidence within the lower range of CTRL. In contrast, if the anterior and superior cerebellum was affected, few or even no CRs were observed. Our findings thus provide evidence that the human cerebellum is required for the acquisition and the retention of this specific conditioned limb-withdrawal reflex. In particular, anterior and superior parts of the cerebellum appear to be involved. Thus, an expansion of the current concept of clinically based, functional compartmentalization is suggested, such that anterior and superior cerebellar regions must be intact to establish plastic changes required for the acquisition of the conditioned withdrawal response. [ABSTRACT FROM AUTHOR]

Background: Classical conditioning of the eyeblink reflex is a simple form of motor learning which depends on the integrity of the cerebellum. Acquistion of conditioned eyeblink responses is markedly impaired in patients with cerebellar disorders. Noninvasive transcranial direct current stimulation (tDCS) has been reported to modify the excitability of the cerebellum (Galea et al., 2009, 2010). The aim of the study was to assess whether acquisition of conditioned eyeblink responses (CRs) is modulated by cerebellar tDCS. Methods: A standard delay conditioning paradigm (a 540ms tone-CS coterminating with a 100ms air-puff-US, 100 paired CS-US trials and 30 extinction CS-alone trials) was used in a total of 30 healthy subjects (18 f, 12 m, mean age 23.4±1.9years). TDCS (2mA intensity, ramp like onset) was applied over the right cerebellar hemisphere ipsilaterally to the US. TDCS was applied during the acquisition phase. Subjects were randomly assigned to 3 groups (n =10) using anodal, cathodal or sham stimulation. The investigator as well as the participants was blinded to the stimulation modality. Results: Compared to sham stimulation mean CR-incidence and learning rate were significantly enhanced by anodal tDCS, whereas onset of CRs occurred significantly earlier. Mean CR incidence and learning rate were significantly reduced in the cathodal stimulation group with no significant changes of timing compared to sham stimulation. Conclusions: In healthy individuals anodal cerebellar tDCS appears to enhance the ability to acquire conditioned eyeblink responses which, however, were less appropriately timed. On the contrary CR-acquisition was markedly decreased by cathodal stimulation. [ABSTRACT FROM AUTHOR]

Highlights: [•] Biomechanical signals show that cerebellar patients exposed to electrical foot stimulation establish conditioned responses. [•] Associative responses in patients were less frequent and smaller than in control subjects. [•] Trajectories of the center of vertical pressure and of body segments are affected in patients. [•] Responses obtained during paired trials are clearly more effective than those recorded during unconditioned stimulus alone. [•] Conditioning stimuli result in motor improvement i.e. shortening of the time of rebalancing and optimizing trajectory loops. [ABSTRACT FROM AUTHOR]

Highlights: [•] Both storage and extinction of learned eyeblink responses showed age-related decline. [•] Age-related decline of storage was related to age-related decline of cerebellar gray matter volume. [•] No significant correlation between extinction and cerebellar gray matter volume was observed. [ABSTRACT FROM AUTHOR]

Abstract: There is increasing evidence of a topographic organization within the human cerebellar cortex for motor and non-motor functions. Likewise, a subdivision of the dentate nucleus in a more dorsal and rostral motor domain and a more ventral and caudal non-motor domain has been proposed by Dum and Strick (2003) based on anatomical studies in monkey. In humans, however, very little is known about topographic organization within the dentate nucleus. Activation of the dentate nucleus in a verb generation task was examined in young and healthy subjects using ultra-highfield 7T functional magnetic resonance imaging (fMRI) with its increase in signal-to-noise ratio. Data of 17 subjects were included in statistical analysis. Subjects were asked to (i) read words (nouns) aloud presented on a screen, (ii) silently read the same nouns, (iii) silently generate the appropriate verbs to the same nouns and (iv) to silently repeat the names of the months. A block design was used. For image processing, a recently developed region of interest (ROI) driven normalization method of the dentate nuclei was applied. Activation related to motor speech (contrast aloud reading minus silent reading) was strongest in the rostral parts of the dentate nucleus. Dorsorostral activations were present bilaterally. Activation related to verb generation (contrast verb generation minus silent reading) was found in the ventrocaudal parts of the dentate nucleus on the right. The present findings are in good accordance with the anatomical data in monkeys and suggest that the human dentate nucleus can be subdivided into a rostral and more dorsal motor domain and a ventrocaudal non-motor domain. [Copyright &y& Elsevier]

The present study investigated dysarthric symptoms in children with cerebellar tumors. Ten children with cerebellar tumors and 10 orthopedic control children were tested prior and one week after surgery. Clinical dysarthric symptoms were quantified in spontaneous speech. Syllable durations were analyzed in syllable repetition and sentence production tasks. Localization of the cerebellar lesions were defined after manual transfer from individual 2D-MR images onto 3D images of a spatially normalized healthy brain. Cerebellar children showed few and mild clinical signs of dysarthria. No difference was present in the sentence production task compared to controls. In five cerebellar children, syllables were prolonged in the syllable repetition task after surgery. Syllable duration normalized in an additional four-week session in all but one case. The MR-analysis showed that superior paravermal cerebellar areas likely involved in dysarthria in adults (paravermal lobules HVI, Crus I) were not significantly affected. In children, speech impairments appear to be rare after cerebellar surgery because tumors most commonly affect posterior-inferior and medial parts of the cerebellum while critical cerebellar regions are likely spared. The results suggest a similar localization of speech functions in the cerebellum in children and adults. [ABSTRACT FROM AUTHOR]

The differential role of the cerebellar cortex and nuclei has rarely been addressed in human lesion and functional brain imaging studies. One important reason is the difficulty of defining the localization of the cerebellar nuclei and extent of possible lesions based on CT or MR scans. The present MRI investigation was specifically designed to study the anatomy of the deep cerebellar nuclei. In both basal ganglia and cerebellar nuclei of healthy human subjects the amount of iron is high compared to the rest of the brain. Clusters of iron are paramagnetic and, therefore, tend to cause local inhomogenities in a magnetic field. The iron-induced susceptibility artefacts were used to visualize the cerebellar nuclei as hypointensities on MR images. A three-dimensional atlas of the dentate (D), interposed (I), and fastigial (F) nuclei is presented in standard proportional stereotaxic space coordinates based on findings in a healthy 26-year-old female. A three-dimensional axial volume of the cerebellum was acquired using a T1-weighted fast low-angle shot (FLASH) sequence on a Siemens Sonata 1.5 Tesla MR. To increase the signal to noise ratio the sequence was acquired 5 times and averaged. Each volume was registered, resampled to 1.00 × 1.00 × 1.00-mm3 voxel size and spatially normalized into a standard proportional stereotaxic space (the MNI-space) using SPM99. Localization of cerebellar nuclei were confirmed by comparison with postmortem MRI and histological microsections of another brain. [Copyright &y& Elsevier]

Background Recently, transcranial direct current stimulation (tDCS) became a popular method to non-invasively modulate cerebellar excitability and help us broaden our understanding of cerebellar functions and introduce new therapeutic applications. Despite its popularity, its parameters, such as current polarity, stimulation intensity and electrode positions to induce specific effects have not yet been standardized. We aimed (1) to test the effects of tDCS with different electrode montages (see below) on cerebellar-brain inhibition (CBI) and (2) to explore the effect of tDCS on specific cerebellar-brain connections measured by the CBI recruitment curve (CBI-RC). Methods 15 and 14 young and healthy participants took part in Experiments 1 and 2, respectively. In all experiments, the target tDCS electrode was placed over the right cerebellar cortex. In Exp. 1, the return electrode over one of the following three positions: the right buccinator muscle, the left supraorbital area or the right deltoid muscle and in Exp. 2, it was positioned over the right buccinator muscle. CBI was measured by double-TMS protocol, with the conditioning stimulus (CS) over the right cerebellum with an intensity of 5% below the brainstem motor threshold (BMT) followed by the test pulse over the left primary motor cortex 5 ms later. For CBI-RC, five different CS intensities were used (−5%, −10%, −15%, −20%, −25% below BMT). The after-effects of 2 mA anodal or cathodal cerebellar tDCS on CBI or CBI-RC in Exp. 1 and 2, respectively, were measured before and for two hours after 15 min of tDCS. Results In Exp. 1, both tDCS polarities significantly decreased CBI for at least two hours compared to both sham and pre-stimulation values. No significant differences between different return electrode positions were observed. In Exp. 2, CBI was significantly increased after anodal and was decreased after cathodal tDCS with low CS intensities in a polarity-specific manner. Conclusions In accordance with the results reported by many studies, our results suggest that the return electrode positioning has no significant impact on the tDCS after-effects. The results of Exp. 2 show that the recruitment of the cerebellar-brain connections varies depending on tDCS polarity and CS intensity, suggesting that tDCS differently affects neurons in different layers of the cerebellar cortex. This polarity-specific dependence should be considered for tDCS applications and addressed in future studies. Funded by Mercur Pr-2015-0010 and SFB1280 (TP A05 and A06). [ABSTRACT FROM AUTHOR]

In the present study, susceptibility weighted imaging (SWI) was used to show atrophy of cerebellar nuclei in spinocerebellar ataxia type 6 (SCA6), Friedreich ataxia (FRDA), and spinocerebellar ataxia type 3 (SCA3). We tested the hypothesis that cerebellar nuclei are smaller in FRDA and SCA3 compared to healthy controls, but relatively preserved in SCA6. In addition, 7T fMRI was performed with optimized normalization methods to assess function of the cerebellar cortex and nuclei during simple hand movements. Twelve SCA6 patients (age range 41–76 years, five female), twelve FRDA patients (age range 21–55 years, seven female), and ten SCA3 patients (age range 34–67 years, three female), and age- and gender-matched control groups (total n = 23, age range 22–75 years, ten female) were included. As expected, volume of the cerebellum was most markedly reduced in SCA6, with no significant reduction in FRDA and a slight decrease in SCA3. Atrophy of the cerebellar nuclei was not only present in FRDA and SCA3, but also in SCA6. In fact, volume reduction of the nuclei was most marked in SCA6. On a functional level, fMRI signal was altered both within the cerebellar cortex and the nuclei in the three disorders. In the nuclei, the reduction was most prominent in FRDA. Different from initial expectations, the decrease of fMRI signal in the cerebellar cortex appeared more prominent in SCA3 and FRDA than in SCA6. These findings will be discussed in further detail in the light of the known pathohistology of the diseases. The study was supported by the EU Marie Curie Initial Training Network (ITN) grant C7 (“Cerebellar-Cortical Control: Cells, Circuits, Computation, and Clinic“). [ABSTRACT FROM AUTHOR]