Consensus Paper: Cerebellum and Ageing.

Given the key roles of the cerebellum in motor, cognitive, and affective operations and given the decline of brain functions with aging, cerebellar circuitry is attracting the attention of the scientific community. The cerebellum plays a key role in timing aspects of both motor and cognitive operations, including for complex tasks such as spatial navigation. Anatomically, the cerebellum is connected with the basal ganglia via disynaptic loops, and it receives inputs from nearly every region in the cerebral cortex. The current leading hypothesis is that the cerebellum builds internal models and facilitates automatic behaviors through multiple interactions with the cerebral cortex, basal ganglia and spinal cord. The cerebellum undergoes structural and functional changes with aging, being involved in mobility frailty and related cognitive impairment as observed in the physio-cognitive decline syndrome (PCDS) affecting older, functionally-preserved adults who show slowness and/or weakness. Reductions in cerebellar volume accompany aging and are at least correlated with cognitive decline. There is a strongly negative correlation between cerebellar volume and age in cross-sectional studies, often mirrored by a reduced performance in motor tasks. Still, predictive motor timing scores remain stable over various age groups despite marked cerebellar atrophy. The cerebello-frontal network could play a significant role in processing speed and impaired cerebellar function due to aging might be compensated by increasing frontal activity to optimize processing speed in the elderly. For cognitive operations, decreased functional connectivity of the default mode network (DMN) is correlated with lower performances. Neuroimaging studies highlight that the cerebellum might be involved in the cognitive decline occurring in Alzheimer's disease (AD), independently of contributions of the cerebral cortex. Grey matter volume loss in AD is distinct from that seen in normal aging, occurring initially in cerebellar posterior lobe regions, and is associated with neuronal, synaptic and beta-amyloid neuropathology. Regarding depression, structural imaging studies have identified a relationship between depressive symptoms and cerebellar gray matter volume. In particular, major depressive disorder (MDD) and higher depressive symptom burden are associated with smaller gray matter volumes in the total cerebellum as well as the posterior cerebellum, vermis, and posterior Crus I. From the genetic/epigenetic standpoint, prominent DNA methylation changes in the cerebellum with aging are both in the form of hypo- and hyper-methylation, and the presumably increased/decreased expression of certain genes might impact on motor coordination. Training influences motor skills and lifelong practice might contribute to structural maintenance of the cerebellum in old age, reducing loss of grey matter volume and therefore contributing to the maintenance of cerebellar reserve. Non-invasive cerebellar stimulation techniques are increasingly being applied to enhance cerebellar functions related to motor, cognitive, and affective operations. They might enhance cerebellar reserve in the elderly. In conclusion, macroscopic and microscopic changes occur in the cerebellum during the lifespan, with changes in structural and functional connectivity with both the cerebral cortex and basal ganglia. With the aging of the population and the impact of aging on quality of life, the panel of experts considers that there is a huge need to clarify how the effects of aging on the cerebellar circuitry modify specific motor, cognitive, and affective operations both in normal subjects and in brain disorders such as AD or MDD, with the goal of preventing symptoms or improving the motor, cognitive, and affective symptoms.

An Appraisal of the Role of the Neocerebellum for Spatial Navigation in Healthy Aging.

Spatial navigation is an intricate ability, requiring multisensory and motor integration, that is particularly impacted in aging. The age-related decline in navigational capabilities is known to be associated with changes in brain regions such as the frontal, temporal, and cerebellar cortices. Age-related cerebellar differences in spatial navigation have generally been ascribed to motor impairments, omitting the central role of this structure in several cognitive processes. In the present voxel-based morphometric study, we investigated gray matter volume loss in older adults across cognitive and motor subregions of the cerebellum. Specifically, we hypothesized that age-related gray matter differences would occur mainly in cerebellar regions involved in cognitive processing. Our results showed a significant age-related atrophy in the left neocerebellum of healthy older adults that includes Crus I and lobule VI. The latter are important nodes in the network that subtends cognitive abilities such as object recognition and spatial cognition. This exploratory work sets the ground for future research to investigate the extent of the neocerebellum's contribution to spatial navigation deficits in aging.

Consensus Paper: Ataxic Gait.

The aim of this consensus paper is to discuss the roles of the cerebellum in human gait, as well as its assessment and therapy. Cerebellar vermis is critical for postural control. The cerebellum ensures the mapping of sensory information into temporally relevant motor commands. Mental imagery of gait involves intrinsically connected fronto-parietal networks comprising the cerebellum. Muscular activities in cerebellar patients show impaired timing of discharges, affecting the patterning of the synergies subserving locomotion. Ataxia of stance/gait is amongst the first cerebellar deficits in cerebellar disorders such as degenerative ataxias and is a disabling symptom with a high risk of falls. Prolonged discharges and increased muscle coactivation may be related to compensatory mechanisms and enhanced body sway, respectively. Essential tremor is frequently associated with mild gait ataxia. There is growing evidence for an important role of the cerebellar cortex in the pathogenesis of essential tremor. In multiple sclerosis, balance and gait are affected due to cerebellar and spinal cord involvement, as a result of disseminated demyelination and neurodegeneration impairing proprioception. In orthostatic tremor, patients often show mild-to-moderate limb and gait ataxia. The tremor generator is likely located in the posterior fossa. Tandem gait is impaired in the early stages of cerebellar disorders and may be particularly useful in the evaluation of pre-ataxic stages of progressive ataxias. Impaired inter-joint coordination and enhanced variability of gait temporal and kinetic parameters can be grasped by wearable devices such as accelerometers. Kinect is a promising low cost technology to obtain reliable measurements and remote assessments of gait. Deep learning methods are being developed in order to help clinicians in the diagnosis and decision-making process. Locomotor adaptation is impaired in cerebellar patients. Coordinative training aims to improve the coordinative strategy and foot placements across strides, cerebellar patients benefiting from intense rehabilitation therapies. Robotic training is a promising approach to complement conventional rehabilitation and neuromodulation of the cerebellum. Wearable dynamic orthoses represent a potential aid to assist gait. The panel of experts agree that the understanding of the cerebellar contribution to gait control will lead to a better management of cerebellar ataxias in general and will likely contribute to use gait parameters as robust biomarkers of future clinical trials.

Selective neural coding of object, feature, and geometry spatial cues in humans.

Orienting in space requires the processing of visual spatial cues. The dominant hypothesis about the brain structures mediating the coding of spatial cues stipulates the existence of a hippocampal-dependent system for the representation of geometry and a striatal-dependent system for the representation of landmarks. However, this dual-system hypothesis is based on paradigms that presented spatial cues conveying either conflicting or ambiguous spatial information and that used the term landmark to refer to both discrete three-dimensional objects and wall features. Here, we test the hypothesis of complex activation patterns in the hippocampus and the striatum during visual coding. We also postulate that object-based and feature-based navigation are not equivalent instances of landmark-based navigation. We examined how the neural networks associated with geometry-, object-, and feature-based spatial navigation compared with a control condition in a two-choice behavioral paradigm using fMRI. We showed that the hippocampus was involved in all three types of cue-based navigation, whereas the striatum was more strongly recruited in the presence of geometric cues than object or feature cues. We also found that unique, specific neural signatures were associated with each spatial cue. Object-based navigation elicited a widespread pattern of activity in temporal and occipital regions relative to feature-based navigation. These findings extend the current view of a dual, juxtaposed hippocampal-striatal system for visual spatial coding in humans. They also provide novel insights into the neural networks mediating object versus feature spatial coding, suggesting a need to distinguish these two types of landmarks in the context of human navigation.

Research Note: Functional Connectivity Between a Corticostriatal Network and the Cerebellum.

BACKGROUND: Basal ganglia and cerebellum are structurally and functionally connected in animals. In humans, tractography and seed-based functional connectivity have confirmed this cerebellar-striatal relation. Independent component analysis (ICA) showed that both cerebellum and basal ganglia take part in distinct intrinsic networks. METHODS: Probabilistic ICA analysis was applied to the brain images of 15 healthy volunteers during the resting state and using a 3 T MRI. RESULTS: A spatial map corresponding to dorsal and ventral basal ganglia circuits was also found to be in functional coherence with crus 2, especially with its vermal region. CONCLUSION: It is speculated that such cerebellar-basal ganglionic rsFC could reflect structural interconnections traced in animals and explain reward-based activity detected in the cerebellum.

Topography of Emotions in Cerebellum as Appraised by Functional Imaging.

Emotions induce complex patterns of cerebellar activity likely reflecting specific cerebellar modulation and multidimensional integration of the emotional experience, based on context-specific dynamic recruitment of limbic, cognitive, mnesic, and sensorimotor cortico-cerebellar loops. Meta-analyses have reported constant recruitment of lobules VI-VII during basic emotions. Activation of rostral lobules II-VI and lobule VIII may be preferentially in relation to motor responses, whereas rostral and caudal vermal activation may be linked to autonomic regulation and associative learning in conjunction with amygdala. Cognitive integration of emotion may rely, at least, on activation of limbic salience network (automatic bottom-up detection of salient stimulus), default-mode network (memory- and knowledge-based categorization), and central executive network (response selection and emotion regulation). As lobules VI-VII straddle all these intrinsically networks, it could be hypothesized that this part of the neocerebellum constitutes an integrator/modulator hub of the emotion-related limbic and cognitive system.

Hidden in the Eyes-Recurrence of Systemic Hemopathies Reportedly "In Remission": Six Cases and Review of Literature.

Background and Objectives: Secondary ocular localizations of hematological malignancies are blinding conditions with a poor prognosis, and often result in a delay in the diagnosis. Materials and Methods: We describe a series of rare cases of ocular involvement in six patients with hematological malignancies, reportedly in remission, who presented secondary ocular localizations, challenging to diagnose. Two patients had an acute lymphoblastic leukemia (ALL) and developed either a posterior scleritis or a pseudo-panuveitis with ciliary process infiltration. One patient had iris plasmacytoma and developed an anterior uveitis as a secondary presentation. Two patients had a current systemic diffuse large B-cell lymphoma (DLBCL) and were referred either for intermediate uveitis or for papilledema and vitritis with secondary retinitis. Finally, one patient with an acute myeloid leukemia (AML) presented a conjunctival localization of a myeloid sarcoma. We herein summarize the current knowledge of ophthalmologic manifestations of extramedullary hematopathies. Results: Inflammatory signs were associated with symptomatic infiltrative lesions well displayed in either the iris, the retina, the choroid, or the cavernous sinus, from the admission of the patients in the ophthalmological department. These findings suggest that patients with ALL, AML, systemic DLBCL, and myeloma can present with ophthalmic involvement, even after having been reported as in remission following an effective systemic treatment and/or allograft. Conclusions: Early detection of hidden recurrence in the eyes may permit effective treatment. Furthermore, oncologists and ophthalmologists should be aware of those rare ocular malignant locations when monitoring patient's progression after initial treatment, and close ophthalmologic examinations should be recommended when detecting patient's ocular symptoms after treatment.

DEEP PHENOTYPING AND FURTHER INSIGHTS INTO ITM2B-RELATED RETINAL DYSTROPHY.

PURPOSE: To reappraise the presentation and the course of ITM2B-related retinal dystrophy and give further insights into ITM2B expression in the retina. METHODS: The clinical data of nine subjects with ITM2B-related retinal dystrophy were retrospectively reviewed. The genetic mutation was assessed for its influence on splicing in cultured fibroblasts. The cellular expression of ITM2B within the inner retina was investigated in wild-type mice through mRNA in situ hybridization. RESULTS: All patients complained of decreased vision and mild photophobia around their twenties-thirties. The peculiar feature was the hyperreflective material on optical coherence tomography within the inner retina and the central outer nuclear layer with thinning of the retinal nerve fiber layer. Although retinal imaging revealed very mild or no changes over the years, the visual acuity slowly decreased with about one Early Treatment Diabetic Retinopathy Study letter per year. Finally, full-field electroretinography showed a mildly progressive inner retinal and cone dysfunction. ITM2B mRNA is expressed in all cellular types of the inner retina. Disease mechanism most likely involves mutant protein misfolding and/or modified protein interaction rather than misplicing. CONCLUSION: ITM2B-related retinal dystrophy is a peculiar, rare, slowly progressive retinal degeneration. Functional examinations (full-field electroretinography and visual acuity) seem more accurate in monitoring the progression in these patients because imaging tends to be stable over the years.

Does the Cerebellum Implement or Select Geometries? A Speculative Note.

During evolution, living systems, actively interacting with their environment, developed the ability, through sensorimotor contingencies, to construct functional spaces shaping their perception and their movements. These geometries were modularly embedded in specific functional neuro-architectures. In particular, human movements were shown to obey several empirical laws, such as the 2/3 power law, isochrony, or jerk minimization principles, which constrain and adapt motor planning and execution. Outstandingly, such laws can be deduced from a combination of Euclidean, affine, and equi-affine geometries, whose neural correlates have been partly detected in several brain areas including the cerebellum and the basal ganglia. Reviving Pellionisz and Llinas general hypothesis regarding the cerebrum and the cerebellum as geometric machines, we speculate that the cerebellum should be involved in implementing and/or selecting task-specific geometries for motor and cognitive skills. More precisely, the cerebellum is assumed to compute forward internal models to help specific cortical and subcortical regions to select appropriate geometries among, at least, Euclidean and affine geometries. We emphasize that the geometrical role of the cerebellum deserves a renewal of interest, which may provide a better understanding of its specific contributions to motor and associative (cognitive) functions.

The Cerebellar Thalamus.

The thalamus is a neural processor and integrator for the activities of the forebrain. Surprisingly, little is known about the roles of the "cerebellar" thalamus despite the anatomical observation that all the cortico-cerebello-cortical loops make relay in the main subnuclei of the thalamus. The thalamus displays a broad range of electrophysiological responses, such as neuronal spiking, bursting, or oscillatory rhythms, which contribute to precisely shape and to synchronize activities of cortical areas. We emphasize that the cerebellar thalamus deserves a renewal of interest to better understand its specific contributions to the cerebellar motor and associative functions, especially at a time where the anatomy between cerebellum and basal ganglia is being rewritten.

Collaboration of Cerebello-Rubral and Cerebello-Striatal Loops in a Motor Preparation Task.

In this study, we used fMRI to identify brain regions associated with concentration (sustained attention) during a motor preparation task. In comparison with a non-concentration task, increased activities were observed (P < 0.05, FWE-corrected P values) in cerebellar lobules VI and VII, motor cortex, pre-supplementary motor area (pre-SMA), thalamus, red nucleus (RN), and caudate nucleus (CN). Moreover, analysis of effective connectivity inter-areal (psychophysiological interactions) showed that during preparation, concentration-related brain activity increase was dependent on Cerebello-thalamo-pre-SMA-RN and Pre-SMA-CN-thalamo-M1 loops. We postulate that, while pre-SMA common to both loops is specifically involved in the movement preparation and readiness for voluntary movement through the striatum, the cerebellar lobule VI in conjunction with RN, likely through a cerebellar-rubro-olivary-cerebellar loop, might be implicated in concentration-related optimization of upcoming motor performances.

MRI of the Optic Nerves and Chiasm in Patients With Leber Hereditary Optic Neuropathy.

BACKGROUND: The aim of this study was to characterize brain and orbital MRI features of patients with Leber hereditary optic neuropathy (LHON), with particular attention to the optic nerves and chiasm. METHOD: We studied a patient cohort with genetically confirmed LHON followed at 2 ophthalmologic hospitals in France between 2013 and 2015. High-resolution brain and orbital MRI studies were analyzed for each patient during the first 12 months after the onset of visual loss was analyzed. RESULTS: Our study included 20 men and 8 women with a mean age of 38.3 years at diagnosis, and all had genetic mutations for LHON. Nineteen patients (67.9%) had T2 hyperintensity in the posterior portion of both optic nerves and in the optic chiasm, and enlargement of the chiasm was found in 16 patients (59.3%). No enhancement of the optic nerves or chiasm was detected. The T2 hyperintensity lesions were not associated with the time between symptom onset and obtaining MRI, the mutation type, or sex of the patient. Nonspecific T2 white matter lesions were found in MRI of 6 patients, but without the characteristics of those found in patients with multiple sclerosis. CONCLUSIONS: Involvement of the posterior portions of the optic nerves has been described previously in case reports of patients with LHON. Our results support this observation with neuroimaging performed within 1 year of onset of visual loss. Enlargement of the optic chiasm also may occur in patients with LHON. The pathophysiology of the MRI changes is not yet understood.

Exploration and Identification of Cortico-Cerebellar-Brainstem Closed Loop During a Motivational-Motor Task: an fMRI Study.

The cerebellum is involved not only in motor coordination, training, and memory, but also in cognition and emotion. Lobule VI in particular belongs to sensorimotor, salience, and executive cerebellar networks. This study aims to determine whether lobule VI would constitute an integrative interface between motor and cognitive/emotional circuits during a motor task with verbal encouragement, likely in conjunction with the basal ganglia (reward and motivational system). We used fMRI to identify specific recruitment of cerebellar and striatal systems during physical performance using two motor tasks with and without encouragement. We found that: (i) Force results were higher during verbal encouragement than during basal condition in all participants. (ii) The anterior part of the right lobule VI was activated by motor execution in both tasks, while its posterior part was specifically activated by verbal encouragement. (iii) The closed-connectivity loop maintained motivation induced by verbal encouragement between cerebral and cerebellar through the red nucleus and striatal network. Therefore, right lobule VI is a hub-controlling sensorimotor and motivates aspects of motor performance in relation with the red nucleus and the ventral striatum. These results could have important implications for extrapyramidal and multisystem degenerative diseases.

Increased functional connectivity between language and visually deprived areas in late and partial blindness.

In the congenitally blind, language processing involves visual areas. In the case of normal visual development however, it remains unclear whether later visual loss induces interactions between the language and visual areas. This study compared the resting-state functional connectivity (FC) of retinotopic and language areas in two unique groups of late visually deprived subjects: (1) blind individuals suffering from retinitis pigmentosa (RP), (2) RP subjects without a visual periphery but with preserved central "tunnel vision", both of whom were contrasted with sighted controls. The results showed increased FC between Broca's area and the visually deprived areas in the peripheral V1 for individuals with tunnel vision, and both the peripheral and central V1 for blind individuals. These findings suggest that FC can develop in the adult brain between the visual and language systems in the completely and partially blind. These changes start in the deprived areas and increase in size (involving both foveal and peripheral V1) and strength (from negative to positive FC) as the disease and sensory deprivation progress. These observations support the claim that functional connectivity between remote systems that perform completely different tasks can change in the adult brain in cases of total and even partial visual deprivation.

The CAM test: a novel tool to quantify the decline in vertical upper limb pointing movements with ageing.

BACKGROUND AND AIM: Although upper limb movements in the vertical plane are very commonly used during the activities of daily life, there is still a lack of a reliable and easy standardized procedure to quantify them. In particular, ageing is associated with a decline in performances of coordinated movements, but a tool to quantify this decline is missing. METHODS: We created a novel portable test called counting arm movement test (CAM test). Participants were asked to perform fast and accurate successive pointing movements towards two fixed targets (mechanical counters) located in a vertical plane in the parasagittal axis during three different time periods (15, 30, 45 s). Each upper limb was assessed separately. The test was evaluated in a group of 63 healthy subjects (mean age ± SD 49.1 ± 19.8 years; F/M 33/30; range 18-87 years). RESULTS: Motor performances (number of clicks) significantly decreased as a function of age for both the dominant side (age effect; linear regression; p < 0.0001 for 15, 30 and 45 s) and the non-dominant side (linear regression; p < 0.0001 for 15, 30 and 45 s). Performances on the dominant and non-dominant side were linearly correlated with the time periods (p < 0.0001 on both sides). The symmetry index (ratio of performance on the dominant side divided by performance on the non-dominant side) was correlated linearly and positively with the duration of the test (y = 0.002x + 1.053; p = 0.0056). We also found a linear relationship between upper limb length and motor performance on the non-dominant side for 15 s (p = 0.023) and 45 s (p = 0.041). The test was characterized by a very high correlation between the results obtained by two investigators during two successive sessions in a subgroup of 7 subjects (Pearson product moment correlation: 0.989 for the dominant side and 0.988 for the non-dominant side). CONCLUSION: The CAM test appears as a robust and low cost tool to quantify upper limb pointing movements. In particular, the test strongly discriminates the effects of age upon motor performances in upper limbs. Future studies are now required to establish the sensitivity, specificity and reliability of this procedure in selected neuromuscular or skeletal diseases affecting the elderly.

Consensus paper: radiological biomarkers of cerebellar diseases.

Hereditary and sporadic cerebellar ataxias represent a vast and still growing group of diseases whose diagnosis and differentiation cannot only rely on clinical evaluation. Brain imaging including magnetic resonance (MR) and nuclear medicine techniques allows for characterization of structural and functional abnormalities underlying symptomatic ataxias. These methods thus constitute a potential source of radiological biomarkers, which could be used to identify these diseases and differentiate subgroups of them, and to assess their severity and their evolution. Such biomarkers mainly comprise qualitative and quantitative data obtained from MR including proton spectroscopy, diffusion imaging, tractography, voxel-based morphometry, functional imaging during task execution or in a resting state, and from SPETC and PET with several radiotracers. In the current article, we aim to illustrate briefly some applications of these neuroimaging tools to evaluation of cerebellar disorders such as inherited cerebellar ataxia, fetal developmental malformations, and immune-mediated cerebellar diseases and of neurodegenerative or early-developing diseases, such as dementia and autism in which cerebellar involvement is an emerging feature. Although these radiological biomarkers appear promising and helpful to better understand ataxia-related anatomical and physiological impairments, to date, very few of them have turned out to be specific for a given ataxia with atrophy of the cerebellar system being the main and the most usual alteration being observed. Consequently, much remains to be done to establish sensitivity, specificity, and reproducibility of available MR and nuclear medicine features as diagnostic, progression and surrogate biomarkers in clinical routine.

Consensus paper: the role of the cerebellum in perceptual processes.

Various lines of evidence accumulated over the past 30 years indicate that the cerebellum, long recognized as essential for motor control, also has considerable influence on perceptual processes. In this paper, we bring together experts from psychology and neuroscience, with the aim of providing a succinct but comprehensive overview of key findings related to the involvement of the cerebellum in sensory perception. The contributions cover such topics as anatomical and functional connectivity, evolutionary and comparative perspectives, visual and auditory processing, biological motion perception, nociception, self-motion, timing, predictive processing, and perceptual sequencing. While no single explanation has yet emerged concerning the role of the cerebellum in perceptual processes, this consensus paper summarizes the impressive empirical evidence on this problem and highlights diversities as well as commonalities between existing hypotheses. In addition to work with healthy individuals and patients with cerebellar disorders, it is also apparent that several neurological conditions in which perceptual disturbances occur, including autism and schizophrenia, are associated with cerebellar pathology. A better understanding of the involvement of the cerebellum in perceptual processes will thus likely be important for identifying and treating perceptual deficits that may at present go unnoticed and untreated. This paper provides a useful framework for further debate and empirical investigations into the influence of the cerebellum on sensory perception.

Proton MR spectroscopy in predicting the increase of perfusion MR imaging for WHO grade II gliomas.

PURPOSE: To investigate the correlation between the metabolite ratios obtained from proton magnetic resonance (MR) spectroscopy and those obtained from MR perfusion parameters (relative cerebral blood volume [rCBV]) in a cohort of low-grade glioma (LGG). MATERIALS AND METHODS: Patients underwent prospectively conventional MR, proton magnetic resonance spectroscopy ((1) HMRS), and perfusion-weighted images (PWI). Statistical analyses were performed to determine the correlative and independent predictive factors of rCBVmax and the metabolite ratio thresholds with optimum sensitivity and specificity. RESULTS: Thirty-one patients were included in this study. Linear correlations were observed between the metabolic ratios (lactate [Lac]/creatine [Cr], choline [Cho]/N-acetyl-aspartate [NAA], free-lipids/Cr) and rCBVmax (P < 0.05). These metabolic ratios were determined to be independent predictive factors of rCBVmax (P = 0.027, 0.011 and 0.032, respectively). According to the receiver operating characteristic curves, the cutoff values of the metabolic ratios to discriminate between the two populations of rCBVmax (<1.7 versus = 1.7) were 1.72, 1.54, and 1.40, respectively, with a sensitivity = 75% and a specificity >95% for Lac/Cr. CONCLUSION: This study demonstrated consistent correlations between the data from (1) HMRS and PWI. The Lac/Cr ratio predicts regional hemodynamic changes, which are themselves a useful biomarker of clinical prognosis in patients with LGG. As such, this ratio may provide a new parameter for making improved clinical decisions.

Functional imaging and the cerebellum: recent developments and challenges. Editorial.

Recent neuroimaging developments allow a better in vivo characterization of the structural and functional connectivity of the human cerebellum. Ultrahigh fields, which considerably increase spatial resolution, enable to visualize deep cerebellar nuclei and cerebello-cortical sublayers. Tractography reconstructs afferent and efferent pathway of the cerebellum. Resting-state functional connectivity individualizes the prewired, parallel close-looped sensorimotor, cognitive, and affective networks passing through the cerebellum. These results are un agreement with activation maps obtained during stimulation functional neuroimaging or inferred from neurological deficits due to cerebellar lesions. Therefore, neuroimaging supports the hypothesis that cerebellum constitutes a general modulator involved in optimizing mental performance and computing internal models. However, the great challenges will remain to unravel: (1) the functional role of red and bulbar olivary nuclei, (2) the information processing in the cerebellar microcircuitry, and (3) the abstract computation performed by the cerebellum and shared by sensorimotor, cognitive, and affective domains.