Cerebellar Signal Research Articles

Ultra-high-field 7-Tesla magnetic resonance imaging in fragile X tremor/ataxia syndrome (FXTAS).

Fragile X tremor/ataxia syndrome (FXTAS) is an adult-onset neurodegenerative disorder characterized by premutation expansion of fragile X mental retardation 1 (FMR1) gene. It is a common single-gene cause of tremor, ataxia, and cognitive decline in adults. FXTAS affects the central, peripheral and autonomic nervous systems, leading to a range of neurological symptoms from dementia to dysautonomia. A characteristic imaging feature of FXTAS is symmetric T2 hyperintensity in the deep white matter of the cerebellar hemispheres and middle cerebral peduncle. However, recent studies have reported additional findings on diffusion weighted images (DWI), such as a symmetric high-intensity band-like signal at the cerebral corticomedullary junction. These findings, along with the characteristic cerebellar signal alterations, overlap with imaging findings seen in adult-onset neuronal intranuclear inclusion disease (NIID). Importantly, recent pathology studies have shown that both FXTAS and NIID can manifest intranuclear inclusion bodies, posing a diagnostic challenge and potential for misdiagnosis. We describe a 58-year-old man with FXTAS who received an erroneous diagnosis based on imaging and histopathology results. We emphasize the potential pitfalls in distinguishing NIID from FXTAS and stress the importance of genetic analysis in all cases with suspected NIID and FXTAS for confirmation. Additionally, we present the 7T MRI brain findings of FXTAS.

Neurocognitive and cerebellar function in ADHD, autism and spinocerebellar ataxia.

The cerebellum plays a major role in balance, motor control and sensorimotor integration, but also in cognition, language, and emotional regulation. Several neuropsychiatric disorders such as attention deficit-hyperactivity disorder (ADHD), autism spectrum disorder (ASD), as well as neurological diseases such as spinocerebellar ataxia type 3 (SCA3) are associated with differences in cerebellar function. Morphological abnormalities in different cerebellar subregions produce distinct behavioral symptoms related to the functional disruption of specific cerebro-cerebellar circuits. The specific contribution of the cerebellum to typical development may therefore involve the optimization of the structure and function of cerebro-cerebellar circuits underlying skill acquisition in multiple domains. Here, we review cerebellar structural and functional differences between healthy and patients with ADHD, ASD, and SCA3, and explore how disruption of cerebellar networks affects the neurocognitive functions in these conditions. We discuss how cerebellar computations contribute to performance on cognitive and motor tasks and how cerebellar signals are interfaced with signals from other brain regions during normal and dysfunctional behavior. We conclude that the cerebellum plays a role in many cognitive functions. Still, more clinical studies with the support of neuroimaging are needed to clarify the cerebellum's role in normal and dysfunctional behavior and cognitive functioning.

Reliability and sensitivity to altered hemodynamics measured with resting-state fMRI metrics: Comparison with 123I-IMP SPECT

Blood oxygenation level-dependent (BOLD) contrast is sensitive to local hemodynamic changes and thus is applicable to imaging perfusion or vascular reactivity. However, knowledge about its measurement characteristics compared to reference standard perfusion imaging is limited. This study longitudinally evaluated perfusion in patients with steno-occlusive disease using resting-state functional MRI (rsfMRI) acquired before and within nine days of anterior circulation revascularization in patients with large cerebral artery steno-occlusive diseases. The reliability and sensitivity to longitudinal changes of rsfMRI temporal correlation (Rc) and time delay (TDc) relative to the cerebellar signal were examined voxel-wise in comparison with single-photon emission CT (SPECT) cerebral blood flow (CBF) using the within-subject standard deviation (Sw) and intraclass correlation coefficients (ICCs). For statistical comparisons, the standard deviation (SD) of longitudinal changes within the cerebellum, the number of voxels with significant changes in the left middle cerebral artery territory ipsilateral to surgery, and their average changes relative to the cerebellar SD were evaluated. The test-retest reliability of the fMRI metrics was also similarly evaluated using the human connectome project (HCP) healthy young adult dataset. The test-retest time interval was 31 ± 18 days. Test-retest reliability was significantly higher for SPECT (cerebellar SD: −2.59 ± 0.20) than for fMRI metrics (cerebellar SD: Rc, −2.34 ± 0.24, p = 0.04; TDc, −2.19 ± 0.21, p = 0.003). Sensitivity to postoperative changes, which was evaluated as the number of voxels, was significantly higher for fMRI TDc (8.78 ± 0.72) than for Rc (7.42 ± 1.48, p = 0.03) or SPECT CBF (6.88 ± 0.67, p < 0.001). The ratio between the average Rc, TDc, and SPECT CBF changes within the left MCA target region and cerebellar SD was also significantly higher for fMRI TDc (1.21 ± 0.79) than Rc (0.48 ± 0.94, p = 0.006) or SPECT CBF (0.23 ± 0.57, p = 0.001). The measurement variability of time delay was also larger than that of temporal correlation in HCP data within the cerebellum (t = −8.7, p < 0.001) or in the whole-brain (t = −27.4, p < 0.001) gray matter. These data suggest that fMRI time delay is more sensitive to the hemodynamic changes than SPECT CBF, although the reliability is lower. The implication for fMRI connectivity studies is that temporal correlation can be significantly decreased due to altered hemodynamics, even in cases with normal CBF.

A cerebellar origin of feedforward inhibition to the motor cortex in non-human primates.

Voluntary movements are driven by coordinated activity across a large population of motor cortical neurons. Formation of this activity is controlled by local interactions and long-range inputs. How remote areas of the brain communicate with motor cortical neurons to effectively drive movement remains unclear. We address this question by studying the cerebellar-thalamocortical system. We find that thalamic input to the motor cortex triggers feedforward inhibition by contacting inhibitory cells via highly effective GluR2-lacking AMPA receptors and that, during task performance, the activity of parvalbumin (PV) and pyramidal cells exhibits relations comparable with movement parameters. We also find that the movement-related activity of PV interneurons precedes firing of pyramidal cells. This counterintuitive sequence of events, where inhibitory cells are recruited more strongly and before excitatory cells, may amplify the cortical effect of cerebellar signals in a way that exceeds their sheer synaptic efficacy by suppressing other inputs.

TBC1D24-related familial infantile multifocal myoclonus: Description of a new Chinese pedigree with a 20 year follow up

IntroductionDisorders associated with mutations in the Tre2/Bub2/Cdc16 (TBC)1 domain family member 24 gene (TBC1D24) present a wide range of phenotypes, ranging from mild to fatal seizure diseases, non-syndromic deafness, and complex syndromes such as deafness, onychodystrophy, osteodystrophy, and mental retardation(DOOR syndrome). In this study, we introduce three siblings of a previously unreported Chinese family with familial infantile myoclonic epilepsy caused by a homozygous TBC1D24 mutation. MethodsGenomic DNA was extracted from whole blood of the proband, his parents, and sisters. TBC1D24 exomes were sequenced by whole exome sequencing then analyzed by genetic analysis with Sanger sequencing validation. The patients were followed up for more than 20 years to summarize their clinical features. ResultsGenetic analysis identified a homozygous TBC1D24 mutation (c.241_252del12) in the proband and his sisters. Prediction models suggest that the mutation leads to an alteration in the properties and structure of the TBC1D24 protein, especially in the folding direction of the loop region, which is likely to decrease protein activity. The patients manifested with early-onset myoclonic epilepsy, were prone to status epilepticus, and seizures only occurred during wakefulness. Imaging characteristics included cerebellar atrophy and abnormal cerebellar signals. ConclusionWe report a pedigree case of infantile myoclonic epilepsy caused by a homozygous TBC1D24 mutation. Our long-term clinical follow-up not only enriches the clinical phenotype of the disease, but also provides a clinical experience for the early diagnosis and clinical treatment of the disease.

Cerebellar signals drive motor adjustments and visual perceptual changes during forward and backward adaptation of reactive saccades.

Saccadic adaptation ($SA$) is a cerebellar-dependent learning of motor commands ($MC$), which aims at preserving saccade accuracy. Since $SA$ alters visual localization during fixation and even more so across saccades, it could also involve changes of target and/or saccade visuospatial representations, the latter ($CDv$) resulting from a motor-to-visual transformation (forward dynamics model) of the corollary discharge of the $MC$. In the present study, we investigated if, in addition to its established role in adaptive adjustment of $MC$, the cerebellum could contribute to the adaptation-associated perceptual changes. Transfer of backward and forward adaptation to spatial perceptual performance (during ocular fixation and trans-saccadically) was assessed in eight cerebellar patients and eight healthy volunteers. In healthy participants, both types of $SA$ altered $MC$ as well as internal representations of the saccade target and of the saccadic eye displacement. In patients, adaptation-related adjustments of $MC$ and adaptation transfer to localization were strongly reduced relative to healthy participants, unraveling abnormal adaptation-related changes of target and $CDv$. Importantly, the estimated changes of $CDv$ were totally abolished following forward session but mainly preserved in backward session, suggesting that an internal model ensuring trans-saccadic localization could be located in the adaptation-related cerebellar networks or in downstream networks, respectively.

A Sweet Imbalance: Reversible Middle Cerebellar Peduncle Signal Change in Hypoglycaemic Encephalopathy.

A Sweet Imbalance: Reversible Middle Cerebellar Peduncle Signal Change in Hypoglycaemic Encephalopathy.

Neural correlates of motor imagery of gait in amyotrophic lateral sclerosis

Gait impairment is understudied and poorly characterised in amyotrophic lateral sclerosis (ALS), despite increasing evidence of considerable extrapyramidal and cerebellar dysfunction. The objective of this study is to assess gait imagery specific-networks and functional adaptation in ALS. Seventeen ALS patients with lower motor neuron predominant (LMNp) disability, fourteen patients with upper motor neurons predominant (UMNp) disease and fourteen healthy controls performed a dual motor imagery task on fMRI; normal and precision. Study-group specific activation patterns were evaluated during motor imagery of gait. Additional voxel based functional connectivity analyses were carried out using the supplementary motor area, cerebellum and striatum as seed regions. Our data revealed a significant increase in imagery time in UMNp patients compared to controls and LMNp during imagined gait. UMNp patients exhibited decreased SMA, DLPFC and superior parietal lobule activation and increased orbitofrontal, parietal and cerebellar signal during imagined locomotion. Increased functional connectivity of the striato and parieto-cerebellar circuits was also demonstrated. Additional activation was detected in the insula and cingulate cortex. The results suggest functional reorganisation in ALS. The study showed that LMNp patients exhibit similar activation patterns to healthy controls during motor imagery of both normal and precision gait. Interestingly, UMNp patients exhibit significantly longer imagery time when they imagined walking on a narrow path (precision gait) and demonstrated gait network alterations compared to LMNp patients and healthy controls. Enhanced striato- and parieto-cerebellar networks in UMNp ALS patients are likely to represent a compensatory response to impaired postural control. Activation of insular and cingulate regions suggest that fear of falling is an implication of gait disturbance in ALS.

Acute Fulminant Cerebellitis in Children with COVID-19 Infection: A Rare But Treatable Complication

Acute Fulminant Cerebellitis in Children with COVID-19 Infection: A Rare But Treatable Complication

Relationship between Signal Intensity of the Labyrinth and Cochleovestibular Testing and Morphologic Features of Vestibular Schwannoma.

Objectives The aim of this article was to evaluate the relationship between signal intensity of the labyrinth and vestibulocochlear function and morphologic features of vestibular schwannoma (VS). Design Cross-sectional Study. Setting Tertiary referral center. Participants Fifty-four patients with sporadic, untreated VS. Main Outcome Measure Signal intensity of the cochlea and vestibule (SIRc and SIRv: signal intensity of cochlea/vestibule compared with cerebellar signal intensity; AURc and AURv: SIRc/SIRv of the affected side compared with the unaffected side) in 1.5T T2-weighted images was correlated with size (Hannover classification), cystic status, distance from the fundus of the internal auditory canal, video head impulse test (vHIT), and audiometry. Results Signal intensity of the vestibule was higher than that of the cochlea ( p < 0.01). Large tumors had lower SIRc than smaller tumors ( p = 0.03); Hannover T1 tumors had higher SIRc ( p < 0.01), SIRv ( p < 0.01), AURc ( p < 0.01) and AURv ( p < 0.01) than the rest; heterogenous and cystic tumors had higher SIRv than solid large tumors ( p = 0.02); superior vestibular nerve pattern on vHIT had higher SIRv and AURv than inferior vestibular nerve and mixed patterns ( p = 0.03 and 0.004, respectively); and there was a weak correlation between AURv and speech discrimination ( r = 0.33, p = 0.04). Conclusion A more abnormal signal intensity of the labyrinth is associated with larger size and solid status of VS. There was a positive relationship between signal intensity of the labyrinth and speech discrimination scores on audiogram.

Neural Correlates of Motor Imagery of Gait in Amyotrophic Lateral Sclerosis.

Gait impairment is poorly characterized in amyotrophic lateral sclerosis (ALS), despite increasing evidence of extrapyramidal and cerebellar dysfunction. Gait impairment adds to the considerable motor disability of ALS patients and requires targeted multidisciplinary interventions. To assess gait imagery-specific networks and functional adaptation in ALS. Prospective. Seventeen ALS patients with lower motor neuron predominant (LMNp) disability, 14 patients with upper motor neurons predominant (UMNp) disease, and 14 healthy controls were included. 3T / gradient echo echo planar (GE-EPI). Subjects performed a dual motor imagery task: normal and precision gait. The Movement Imagery Questionnaire - Revised Second Version (MIQ-rs) was used to appraise movement imagery in each participant. Study group-specific activation patterns were evaluated during motor imagery of gait. Additional generalized psychophysiological interaction analyses were carried out using the supplementary motor area, caudate, cerebellum, and superior parietal lobule as seed regions. Repeated-measures analysis of variance (ANOVA) was used to compare time imagery and MIQ-rs scores between groups. Size effects were also reported as partial eta squared (η2). One-way ANOVA was performed to explore differences in terms of connexions during motor imagery tasks. A significant increase in imagery time in UMNp patients compared to controls (P < 0.05) and LMNp (P < 0.05) during imagined gait was demonstrated. UMNp patients exhibited altered supplementary motor area, precentral gyrus, superior parietal lobule, and dorsolateral prefrontal cortex activation and increased orbitofrontal (pFDR(False Discovery Rate) < 0.05), posterior parietal (pFDR < 0.05) caudate (pFDR < 0.05), and cerebellar (pFDR < 0.05) signal during imagined locomotion. Increased effective connectivity of the striato-cerebellar and parieto-cerebellar circuits was also demonstrated. Additional activation was detected in the insula and cingulate cortex. Enhanced striato- and parieto-cerebellar networks in UMNp ALS patients are likely to represent a compensatory response to impaired postural control. 2 TECHNICAL EFFICACY STAGE: 5.

Cerebellar Watershed Injury in Children.

Focal signal abnormalities at the depth of the cerebellar fissures in children have recently been reported to represent a novel pattern of bottom-of-fissure dysplasia. We describe a series of patients with a similar distribution and appearance of cerebellar signal abnormality attributable to watershed injury. Twenty-three children with MR imaging findings of focal T2 prolongation in the cerebellar gray matter and immediate subjacent white matter at the depth of the fissures were included. MR imaging examinations were qualitatively analyzed for the characteristics and distribution of signal abnormality within posterior fossa structures, the presence and distribution of volume loss, the presence of abnormal contrast enhancement, and the presence and pattern of supratentorial injury. T2 prolongation was observed at the depths of the cerebellar fissures bilaterally in all 23 patients, centered at the expected location of the deep cerebellar vascular borderzone. Diffusion restriction was associated with MR imaging performed during acute injury in 13/16 patients. Five of 23 patients had prior imaging, all demonstrating a normal cerebellum. The etiology of injury was hypoxic-ischemic injury in 17/23 patients, posterior reversible encephalopathy syndrome in 3/23 patients, and indeterminate in 3/23 patients. Twenty of 23 patients demonstrated an associated classic parasagittal watershed pattern of supratentorial cortical injury. Injury in the chronic phase was associated with relatively preserved gray matter volume in 8/15 patients, closely matching the published appearance of bottom-of-fissure dysplasia. In a series of patients with findings similar in appearance to the recently described bottom-of-fissure dysplasia, we have demonstrated a stereotyped pattern of injury attributable to cerebellar watershed injury.

Detectability of cerebellar activity with magnetoencephalography and electroencephalography.

Electrophysiological signals from the cerebellum have traditionally been viewed as inaccessible to magnetoencephalography (MEG) and electroencephalography (EEG). Here, we challenge this position by investigating the ability of MEG and EEG to detect cerebellar activity using a model that employs a high‐resolution tessellation of the cerebellar cortex. The tessellation was constructed from repetitive high‐field (9.4T) structural magnetic resonance imaging (MRI) of an ex vivo human cerebellum. A boundary‐element forward model was then used to simulate the M/EEG signals resulting from neural activity in the cerebellar cortex. Despite significant signal cancelation due to the highly convoluted cerebellar cortex, we found that the cerebellar signal was on average only 30–60% weaker than the cortical signal. We also made detailed M/EEG sensitivity maps and found that MEG and EEG have highly complementary sensitivity distributions over the cerebellar cortex. Based on previous fMRI studies combined with our M/EEG sensitivity maps, we discuss experimental paradigms that are likely to offer high M/EEG sensitivity to cerebellar activity. Taken together, these results show that cerebellar activity should be clearly detectable by current M/EEG systems with an appropriate experimental setup.

Erratum: Soda et al., "Hyperexcitability and Hyperplasticity Disrupt Cerebellar Signal Transfer in the IB2 KO Mouse Model of Autism".

Erratum: Soda et al., "Hyperexcitability and Hyperplasticity Disrupt Cerebellar Signal Transfer in the IB2 KO Mouse Model of Autism".

Hyperexcitability and Hyperplasticity Disrupt Cerebellar Signal Transfer in the IB2 KO Mouse Model of Autism.

Autism spectrum disorders (ASDs) are pervasive neurodevelopmental conditions that often involve mutations affecting synaptic mechanisms. Recently, the involvement of cerebellum in ASDs has been suggested, but the underlying functional alterations remained obscure. We investigated single-neuron and microcircuit properties in IB2 (Islet Brain-2) KO mice of either sex. The IB2 gene (chr22q13.3 terminal region) deletion occurs in virtually all cases of Phelan-McDermid syndrome, causing autistic symptoms and a severe delay in motor skill acquisition. IB2 KO granule cells showed a larger NMDA receptor-mediated current and enhanced intrinsic excitability, raising the excitatory/inhibitory balance. Furthermore, the spatial organization of granular layer responses to mossy fibers shifted from a "Mexican hat" to a "stovepipe hat" profile, with stronger excitation in the core and weaker inhibition in the surround. Finally, the size and extension of long-term synaptic plasticity were remarkably increased. These results show for the first time that hyperexcitability and hyperplasticity disrupt signal transfer in the granular layer of IB2 KO mice, supporting cerebellar involvement in the pathogenesis of ASD.SIGNIFICANCE STATEMENT This article shows for the first time a complex set of alterations in the cerebellum granular layer of a mouse model [IB2 (Islet Brain-2) KO] of autism spectrum disorders. The IB2 KO in mice mimics the deletion of the corresponding gene in the Phelan-McDermid syndrome in humans. The changes reported here are centered on NMDA receptor hyperactivity, hyperplasticity, and hyperexcitability. These, in turn, increase the excitatory/inhibitory balance and alter the shape of center/surround structures that emerge in the granular layer in response to mossy fiber activity. These results support recent theories suggesting the involvement of cerebellum in autism spectrum disorders.

A subcortical circuit linking the cerebellum to the basal ganglia engaged in vocal learning.

Speech is a complex sensorimotor skill, and vocal learning involves both the basal ganglia and the cerebellum. These subcortical structures interact indirectly through their respective loops with thalamo-cortical and brainstem networks, and directly via subcortical pathways, but the role of their interaction during sensorimotor learning remains undetermined. While songbirds and their song-dedicated basal ganglia-thalamo-cortical circuitry offer a unique opportunity to study subcortical circuits involved in vocal learning, the cerebellar contribution to avian song learning remains unknown. We demonstrate that the cerebellum provides a strong input to the song-related basal ganglia nucleus in zebra finches. Cerebellar signals are transmitted to the basal ganglia via a disynaptic connection through the thalamus and then conveyed to their cortical target and to the premotor nucleus controlling song production. Finally, cerebellar lesions impair juvenile song learning, opening new opportunities to investigate how subcortical interactions between the cerebellum and basal ganglia contribute to sensorimotor learning.

Realization of Direction Selective Motor Learning in the Artificial Cerebellum: Simulation on the Vestibuloocular Reflex Adaptation.

The vestibule-ocular reflex (VOR) has been one of the most popular model systems to investigate the role of the cerebellum in adaptive motor control. VOR motor learning can be experimentally induced by continuous application of combination of head rotating stimulus and optokinetic stimulus. For instance, in phase application of those stimuli decreases VOR gain defined by eye velocity of VOR in the dark divided by head velocity, while out of phase of those increases VOR gain. It has been known that VOR gain is modifiable context-dependently. Namely, VOR gains for leftward and rightward head rotations can be respectively increased and decreased simultaneously. The cerebellar signal processing underlying the context dependent VOR motor learning, however, is not fully uncovered. In the present study, we simulated direction selective VOR motor learning, using the artificial cerebellar neuronal network model that we developed to understand the origin of the cerebellar motor learning.

Neuromagnetic Cerebellar Activity Entrains to the Kinematics of Executed Finger Movements

This magnetoencephalography (MEG) study aims at characterizing the coupling between cerebellar activity and the kinematics of repetitive self-paced finger movements. Neuromagnetic signals were recorded in 11 right-handed healthy adults while they performed repetitive flexion-extensions of right-hand fingers at three different movement rates: slow (~ 1Hz), medium (~ 2Hz), and fast (~ 3Hz). Right index finger acceleration was monitored with an accelerometer. Coherence analysis was used to index the coupling between right index finger acceleration and neuromagnetic signals. Dynamic imaging of coherent sources was used to locate coherent sources. Coupling directionality between primary sensorimotor (SM1), cerebellar, and accelerometer signals was assessed with renormalized partial directed coherence. Permutation-based statistics coupled with maximum statistic over the entire brain volume or restricted to the cerebellum were used. At all movement rates, maximum coherence peaked at SM1 cortex contralateral to finger movements at movement frequency (F0) and its first harmonic (F1). Significant (statistics restricted to the cerebellum) coherence consistently peaked at the right posterior lobe of the cerebellum at F0 with no influence of movement rate. Coupling between Acc and cerebellar signals was significantly stronger in the afferent than in the efferent direction with no effective contribution of cortico-cerebellar or cerebello-cortical pathways. This study demonstrates the existence of significant coupling between finger movement kinematics and neuromagnetic activity at the posterior cerebellar lobe ipsilateral to finger movement at F0. This coupling is mainly driven by spinocerebellar, presumably proprioceptive, afferences.

Sex differences in cerebellar synaptic transmission and sex-specific responses to autism-linked Gabrb3 mutations in mice.

Neurons of the cerebellar nuclei (CbN) transmit cerebellar signals to premotor areas. The cerebellum expresses several autism-linked genes, including GABRB3, which encodes GABAA receptor β3 subunits and is among the maternal alleles deleted in Angelman syndrome. We tested how this Gabrb3 m-/p+ mutation affects CbN physiology in mice, separating responses of males and females. Wild-type mice showed sex differences in synaptic excitation, inhibition, and intrinsic properties. Relative to females, CbN cells of males had smaller synaptically evoked mGluR1/5-dependent currents, slower Purkinje-mediated IPSCs, and lower spontaneous firing rates, but rotarod performances were indistinguishable. In mutant CbN cells, IPSC kinetics were unchanged, but mutant males, unlike females, showed enlarged mGluR1/5 responses and accelerated spontaneous firing. These changes appear compensatory, since mutant males but not females performed indistinguishably from wild-type siblings on the rotarod task. Thus, sex differences in cerebellar physiology produce similar behavioral output, but provide distinct baselines for responses to mutations.

P37. Effects of acetyl-dl-leucine on the cerebral activation pattern in cerebellar ataxia (FDG-PET study)

Introduction A recent case series study showed significant improvements of symptoms in patients with cerebellar ataxia on medication with the amino acid acetyl-dl-leucine (Tanganil) (Strupp et al., 2013). In analogy to electrophysiological studies in animals it was hypothesized that acetyl-DL-leucine modulates the activity of central vestibular neurons, preferably in the cerebellum, by normalizing the membrane potential of depolarized or hyperpolarized neurons and thereby improves central compensation. However, the mode of action of acetyl-dl-leucine and the site of central compensation remained speculative. To deepen our insights in the central compensatory processes induced by acetyl-dl-leucine we performed a FDG-PET study in cerebellar ataxic patients off and on treatment. Methods 21 patients with cerebellar ataxia of different etiologies were scanned by resting state FDG-PET twice, (A) off treatment (PET 1), and a second time (B) ⩾3months on treatment with 5g/day acetyl-dl-leucine (PET 2; n =18). At both time points the patients underwent a detailed neurological examination and measurements of standardized ataxia scales (SARA, SCAFI). Group subtraction analyses (PET 1 vs. PET 2; responders vs. non-responders) as well as statistical group comparisons with age- and gender-matched healthy controls were calculated with statistical parametric mapping (SPM). Results The contrast on vs. off treatment (PET 2 vs. PET 1) mainly showed signal differences in the mesencephalon (midbrain integration centers) as well as in the lateral medullary brainstem (vestibular nucleus region), thalami and midinsular regions bilaterally. The contrast PET 1 vs. PET 2 revealed signal differences in the posterior insula as well as in primary and secondary visual areas (including MT/V5) bilaterally. Restricting the analyses to treatment-responders ( n =11), PET 2 vs. PET 1 showed similar signal areas in the central midbrain and dorsal medullary brainstem bilaterally that were lacking in the corresponding contrast of the non-responders ( n =6). In the direct comparison of responders vs. non-responders PET 2 signal differences were located in both caudate nuclei, the superior temporal gyrus and hippocampus. The signal in responders – mainly in the posterior insula and the medial temporal gyrus – was lower compared to non-responders. In all contrasts cerebellar signal changes were sparse. Conclusions Central compensatory processes induced by acetyl-dl-leucine in cerebellar ataxia seem to involve mainly centers in the medulla (vestibular nuclei), midbrain (vestibular integration centers), thalami, basal ganglia and insular regions rather than neurons in the cerebellum, the primary site of dysfunction in cerebellar ataxia syndromes.