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... Upon her re-admission 1 month later, the patient's major complaint was worsening of the ataxia and an increased cognitive-emotional deficit. In recent years, increasing evidence for a role for the cerebellum in emotion and cognition has emerged [8][9][10][11][12] and the patient was identified as having cerebellar cognitive affective syndrome [13]. The default mode network (DMN) has become the primary and most popular target of resting state networks and is thought to be involved in advanced cognitive functions and emotion [14][15][16]. ...
... Most of these are part of the DMN described above and involved in processing of cognition and emotions. Additional insight was derived from VBM studies [9,26]. For example, Olivito et al. assessed the relationship between cerebellar gray matter (GM) atrophy and neuropsychological scores in patients with spinocerebellar ataxia 2 using VBM and found GM loss in the cognitive posterior lobules (VI, Crus I, Crus II, VIIB, and IX) that correlated with visuospatial, verbal memory, and executive tasks [26]. ...
... Fig. 1 Clinical and imaging features of cerebellar ataxia patient associated with anti-Tr/DNER antibodies. A: The symptoms and treatment measures of the patient; B: VBM analysis showed reduced cerebellar volume bilaterally, especially in the posterior lobe and uvula of cerebellum, and the middle of the left temporal lobe compared with controls; C: The seed-based FC investigation showed lower connectivity between posterior cingulate cortex (PCC)/precuneus and left frontal lobe than that of the control group; D: Brain PET-CT showed obvious decreased fluorodeoxyglucose (FGD) uptake in bilateral cerebellum; E: whole-body PET-CT showed no malignant changes were found fMRI studies that showed altered FC between cerebellar and cerebrum regions, which are known to be related to cognition and emotion, in patients with spinocerebellar ataxia 2, depression, and Alzheimer's disease [9,[27][28][29][30]. In our patient, VBM analysis revealed atrophy in both the DMN structure and cerebellum. ...
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Background Brain magnetic resonance imaging (MRI) rarely reveals structural changes in patients with suspected anti-Tr/DNER encephalitis and thus provides very limited information. Here, we combined structural MRI, functional MRI, and positron emission tomography-computed tomography (PET-CT) findings to characterize this rare disorder in a patient. Case presentation A 43-year-old woman presented with progressive cerebellar ataxia, memory impairment, anxiety, and depression. Anti-Tr antibodies were detected in both her serum (1:10) and cerebrospinal fluid (1:10). A diagnosis of anti-Tr-positive autoimmune cerebellar ataxia was established. The patient’s symptoms were worse, but her brain MRI was normal. Meanwhile, voxel-based morphometry analysis showed bilateral reduced cerebellar volume, especially in the posterior lobe and uvula of the cerebellum and the middle of the left temporal lobe compared with 6 sex- and age-matched healthy subjects (6 females, 43 ± 2 years; p < 0.05). Using seed-based functional connectivity analysis, decreased connectivity between the posterior cingulate cortex/precuneus and left frontal lobe compared to the control group ( p < 0.05) was detected. PET-CT revealed bilateral hypometabolism in the cerebellum and relative hypermetabolism in the cerebellar vermis and bilateral frontal lobe, but no malignant changes. Conclusions A combination of structural MRI, functional MRI, and brain PET-CT has higher diagnostic and prognostic value than conventional MRI in patients with suspected anti-Tr/DNER encephalitis.
... A link between the cerebellum and attention has also been reported [21][22][23]. Attentional deficits are frequently associated with the presence of morphological cerebellar abnormalities, as observed in patients with autism spectrum disorders and attention deficit hyperactivity disorder [24][25][26] or in cerebellar neurodegenerative disorders [22]. Moreover, previous neuropsychological reports described the role played by the cerebellum in attention, particularly in the coordination of attentional shifts [12,[27][28][29] and selective attention [30,31]. ...
... A link between the cerebellum and attention has also been reported [21][22][23]. Attentional deficits are frequently associated with the presence of morphological cerebellar abnormalities, as observed in patients with autism spectrum disorders and attention deficit hyperactivity disorder [24][25][26] or in cerebellar neurodegenerative disorders [22]. Moreover, previous neuropsychological reports described the role played by the cerebellum in attention, particularly in the coordination of attentional shifts [12,[27][28][29] and selective attention [30,31]. ...
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The functional domain of the cerebellum extends beyond its traditional role in motor control. In recent years, this structure has increasingly been considered to play a crucial role even in cognitive performance and attentional processes. Attention is defined as the ability to appropriately allocate processing resources to relevant stimuli. According to the Posnerian model, three interacting networks modulate attentive processes: the alerting, orienting, and executive networks. The aim of this study was to investigate the role played by the cerebellum in the functioning of the attentive networks using the Attention Network Test (ANT). We studied the effects of transcranial direct current stimulation (tDCS), delivered over the cerebellum in cathodal, anodal, and sham sessions, on ANT parameters in healthy subjects. After anodal and sham tDCS, the efficiency of the three attention networks remained stable, and a significant reduction in reaction time (RT) following the task repetition was observed for both congruent and incongruent targets, indicating a learning effect. After cathodal stimulation, instead, while the efficiency of the alerting and orienting networks remained stable, the efficiency of the executive network was significantly reduced. Moreover, a significant reduction in RT was observed for the congruent target alone, with no difference being detected for the incongruent target, indicating that cerebellar inhibition caused an attentive executive dysfunction specifically related to the ability to process complex stimuli in which conflict signals or errors are present. These results point to a role of the cerebellum, a subcortical structure that is thought to affect error processing both directly, by making predictions of errors or behaviors related to errors, and indirectly, by managing the functioning of brain cortical areas involved in the perception of conflicting signals, in the functioning of the attentional networks, particularly the executive network.
... The DN alteration is of particular interest, given the cerebellar anatomy. Indeed, the DN is the major cerebellar output channel connecting to the cerebral cortex (8), and modifications in functional connectivity (FC) within specific cerebello-cortical networks have already been described in patients affected by other forms of cerebellar atrophy (9)(10)(11)(12) and linked to motor, cognitive, and behavioral symptoms (13)(14)(15)(16)(17)(18)(19)(20)(21)(22). ...
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Spastic paraplegia type 7 (SPG7), which represents one of the most common forms of autosomal recessive spastic paraplegia (MIM#607259), often manifests with a complicated phenotype, characterized by progressive spastic ataxia with evidence of cerebellar atrophy on brain MRI. Recent studies have documented the presence of peculiar dentate nucleus hyperintensities on T2-weighted images and frontal executive dysfunction in neuropsychological tests in SPG7 patients. Therefore, we decided to assess whether any particular MRI pattern might be specifically associated with SPG7 mutations and possibly correlated with patients' cognitive profiles. For this purpose, we evaluated six SPG7 patients, studying the cerebello-cortical network by MRI voxel-based morphometry and functional connectivity techniques, compared to 30 healthy control subjects. In parallel, we investigated the cognitive and social functioning of the SPG7 patients. Our results document specific cognitive alterations in language, verbal memory, and executive function in addition to an impairment of social task and emotional functions. The MRI scans showed a diffuse symmetric reduction in the cerebellar gray matter of the right lobule V, right Crus I, and bilateral lobule VI, together with a cerebral gray matter reduction in the lingual gyrus, precuneus, thalamus, and superior frontal gyrus. The evidence of an over-connectivity pattern between both the right and left cerebellar dentate nuclei and specific cerebral regions (the lateral occipital cortex, precuneus, left supramarginal gyrus, and left superior parietal lobule) confirms the presence of cerebello-cortical dysregulation in different networks involved in cognition and social functioning in SPG7 patients.
... In recent years, an increasing body of studies focused on the cerebellar role in cognitive functions and emotional regulation also including social cognition abilities [1][2][3][4][5][6][7][8][9][10]. From an anatomical point of view, research documented the existence of reciprocal connections between specific cerebellar regions and associative and paralimbic cerebral structures related to emotional and social processing such as the temporo-parietal junction (TPJ), the lateral temporal cortex, the posterior cingulate cortex, the inferior frontal gyrus [11], the amygdala [12], and the insula [13]. ...
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In recent years, increasing evidence of the cerebellar role in social cognition has emerged. The cerebellum has been shown to modulate cortical activity of social brain regions serving as a regulator of function-specific mentalizing and mirroring processes. In particular, a mentalizing area in the posterior cerebellum, specifically Crus II, is preferentially recruited for more complex and abstract forms of social processing, together with mentalizing cerebral areas including the dorsal medial prefrontal cortex (dmPFC), the temporo-parietal junction (TPJ), and the precuneus. In the present study, the network-based statistics approach was used to assess functional connectivity (FC) differences within this mentalizing cerebello-cerebral network associated with a specific cerebellar damage. To this aim, patients affected by spinocerebellar ataxia type 2 (SCA2), a neurodegenerative disease specifically affecting regions of the cerebellar cortex, and age-matched healthy subjects have been enrolled. The dmPFC, left and right TPJ, the precuneus, and the cerebellar Crus II were used as regions of interest to construct the mentalizing network to be analyzed and evaluate pairwise functional relations between them. When compared with controls, SCA2 patients showed altered internodal connectivity between dmPFC, left (L-) and right (R-) TPJ, and right posterior cerebellar Crus II. The present results indicate that FC changes affect a function-specific mentalizing network in patients affected by cerebellar damage. In particular, they allow to better clarify functional alteration mechanisms driven by the cerebellar damage associated with SCA2 suggesting that selective cortico-cerebellar functional disconnections may underlie patients’ social impairment in domain-specific complex and abstract forms of social functioning.
... Another recent VBM study has shown the significant gray matter loss in the bilateral regions of the anterior cerebellar hemisphere (I-V), the posterior lobe (VI-IX), and the posterior vermis (VI-IX). In this research, it was proposed that there is a selective topography between the cerebellar lobules and the specific attentional impairments, namely, the attention deficits observed in SCA2 patients are caused by the dysfunction of cerebrocerebellar circuitry and the specific site of the cerebellar degeneration is also involved [73]. The VBM-based quantitative analysis of the degeneration patterns revealed that the degeneration was clearly localized to the lobules VII to IX in SCA2 patients representing a unique degeneration signature in the cerebellar cortex that determines the unique symptomology in SCA2 [74]. ...
Article
The effective therapeutic treatment and the disease-modifying therapy for spinocerebellar ataxia type 2 (SCA2) (a progressive hereditary disease caused by an expansion of polyglutamine in the ataxin-2 protein) is not available yet. At present, only symptomatic treatment and methods of palliative care are prescribed to the patients. Many attempts were made to study the physiological, molecular, and biochemical changes in SCA2 patients and in a variety of the model systems to find new therapeutic targets for SCA2 treatment. A better understanding of the uncovered molecular mechanisms of the disease allowed the scientific community to develop strategies of potential therapy and helped to create some promising therapeutic approaches for SCA2 treatment. Recent progress in this field will be discussed in this review article.
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Clinical studies described emotional and social behaviour alterations in patients with cerebellar diseases, proposing a role of specific cerebello-cerebral circuits in social cognition. However, for a long time these difficulties were underestimated, and no studies have addressed the correlation between social cognition deficits and topography of the cerebellar damage. The present study aims to investigate the social cognition impairment and the neuroanatomical alterations in patients with spinocerebellar ataxia type 2 (SCA2) and to analyze their relationship. To this purpose a social cognition battery composed by three tests, and a MRI protocol were administered to 13 SCA2 patients and 26 healthy subjects. The pattern of gray matter (GM) atrophy was analyzed by voxel-based morphometry, and the GM volumes of each altered area were correlated with the behavioral scores to investigate anatomo-functional relationships. In addition, we investigated the relationship between social deficits and damage to the cerebellar peduncles using DTI diffusivity indices.Our patients showed impairment of the immediate perceptual component of the mental state recognition (i.e. to recognize feelin gs and thoughts from the eyes expression), and difficulties in anger attribution, and in the understanding of false or mistaken beliefs. They showed a pattern of GM reduction in specific cerebellar regions, including lobules IX and VIIIb and Crus II, all of which are involved in specific components of the mentalizing process. Interestingly, the behavioral performance, in which SCA2 patients showed impairments compared to controls, correlated with the degree of cerebellar GM reduction and with the presence of microstructural abnormalities in the cerebellar peduncles. The present study provides the first characterization of some areas of the social cognition deficits in a homogenous cohort SCA2 patients and demonstrates that alterations in specific cerebellar regions should represent the neurobiological underpinning of their social behavior difficulties. Our results offer a new point of view in considering these aspects in the clinical practice.
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Disinhibition, mainly caused by damage in frontotemporal brain regions, is one of the major causes of caregiver distress in neurodegenerative dementias. Behavioural inhibition deficits are usually described as a loss of social conduct and impulsivity, whereas cognitive inhibition deficits refer to impairments in the suppression of prepotent verbal responses and resistance to distractor interference. In this review, we aim to discuss inhibition deficits in neurodegenerative dementias through behavioural, cognitive, neuroanatomical and neurophysiological exploration. We also discuss impulsivity and compulsivity behaviours as related to disinhibition. We will therefore describe different tests available to assess both behavioural and cognitive disinhibition and summarise different manifestations of disinhibition across several neurodegenerative diseases (behavioural variant of frontotemporal dementia, Alzheimer’s disease, Parkinson’s disease, progressive supranuclear palsy, Huntington’s disease). Finally, we will present the latest findings about structural, metabolic, functional, neurophysiological and also neuropathological correlates of inhibition impairments. We will briefly conclude by mentioning some of the latest pharmacological treatment options available for disinhibition. Within this framework, we aim to highlight i) the current interests and limits of tests and questionnaires available to assess behavioural and cognitive inhibition in clinical practice and in clinical research; ii) the interpretation of impulsivity and compulsivity within the spectrum of inhibition deficits; and iii) the brain regions and networks involved in such behaviours.
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Objective To investigate cognitive inhibition in presymptomatic C9orf72 mutation carriers (C9+) and its associated neuroanatomical correlates. Methods Thirty-eight presymptomatic C9orf72 mutation carriers (C9+, mean age 38.2±8.0 years) and 22 C9− controls from the PREV-DEMALS cohort were included in this study. They underwent a cognitive inhibition assessment with the Hayling Sentence Completion Test (HSCT; time to completion (part B−part A); error score in part B) as well as a 3D MRI. Results C9+ individuals younger than 40 years had higher error scores (part B) but equivalent HSCT time to completion (part B−part A) compared to C9− individuals. C9+ individuals older than 40 years had both higher error scores and longer time to completion. HSCT time to completion significantly predicted the proximity to estimated clinical conversion from presymptomatic to symptomatic phase in C9+ individuals (based on the average age at onset of affected relatives in the family). Anatomically, we found that HSCT time to completion was associated with the integrity of the cerebellum. Conclusion The HSCT represents a good marker of cognitive inhibition impairments in C9+ and of proximity to clinical conversion. This study also highlights the key role of the cerebellum in cognitive inhibition.
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Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant neurodegenerative disease involving the cerebellum and characterized by a typical motor syndrome. In addition, the presence of cognitive impairment is now widely acknowledged as a feature of SCA2. Given the extensive connections between the cerebellum and associative cerebral areas, it is reasonable to hypothesize that cerebellar neurodegeneration associated with SCA2 may impact on the cerebellar modulation of the cerebral cortex, thus resulting in functional impairment. The aim of the present study was to investigate and quantitatively map the pattern of cerebellar gray matter (GM) atrophy due to SCA2 neurodegeneration and to correlate that with patients’ cognitive performances. Cerebellar GM maps were extracted and compared between SCA2 patients (n = 9) and controls (n = 33) by using voxel-based morphometry. Furthermore, the relationship between cerebellar GM atrophy and neuropsychological scores of the patients was assessed. Specific cerebellar GM regions were found to be affected in patients. Additionally, GM loss in cognitive posterior lobules (VI, Crus I, Crus II, VIIB, IX) correlated with visuospatial, verbal memory and executive tasks, while additional correlations with motor anterior (V) and posterior (VIIIA, VIIIB) lobules were found for the tasks engaging motor and planning components. Our results provide evidence that the SCA2 neurodegenerative process affects the cerebellar cortex and that MRI indices of atrophy in different cerebellar subregions may account for the specificity of cognitive symptomatology observed in patients, as result of a cerebello-cerebral dysregulation.
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Spinocerebellarataxiatype2(SCA2) is an autosomal dominant neurodegenerative disease involving the cerebellum. The particular atrophy pattern results in some typical clinical features mainly including motor deficits. In addition, the presence of cognitive impairments, involving language, visuospatial and executive functions, has been also shown in SCA2 patients and it is now widely accepted as a feature of the disease. The aim of the study is to investigate the microstructural patterns and the anatomo-functional substrate that could account for the cognitive symptomatology observed in SCA2 patients. In the present study, Diffusion tensor imaging (DTI) based-tractography was performed to map the main cerebellar white matter bundles, such as Middle and Superior Cerebellar Peduncles, connecting cerebellum with higher-order cerebral regions. Damage-related diffusivity measures were used to determine the pattern of pathological changes of cerebellar white matter microstructure in patients affected by SCA2 and correlated with the patients' cognitive scores. Our results provide the first evidence that white matter (WM) diffusivity is altered in the presence of the cerebellar cortical degeneration associated with SCA2 thus resulting in a cerebello-cerebral dysregulation that may account for the specificity of cognitive symptomatology observed in patients.
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The cognitive control of movement suppression, including performance monitoring, is one of the core properties of the executive system. A complex cortical and subcortical network involving cerebral cortex, thalamus, subthalamus, and basal ganglia has been regarded as the neural substrate of inhibition of programmed movements. Using the countermanding task, a suitable tool to explore behavioral components of movement suppression, the contribution of the cerebellum in the proactive control and monitoring of voluntary action has been recently described in patients affected by focal lesions involving in particular the cerebellar dentate nucleus. Here, we evaluated the performance on the countermanding task in a group of patients with cerebellar degeneration, in which the cerebellar cortex was diffusely affected, and showed that they display additionally a longer latency in countermanding engaged movements. Overall, the present data confirm the role of the cerebellum in executive control of action inhibition by extending the contribution to reactive motor suppression.
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Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant neurodegenerative disease characterized by a progressive cerebellar syndrome, which can be isolated or associated with extracerebellar signs. It has been shown that patients affected by SCA2 present also cognitive impairments and psychiatric symptoms. The cerebellum is known to modulate cortical activity and to contribute to distinct functional networks related to higher-level functions beyond motor control. It is therefore conceivable that one or more networks, rather than isolated regions, may be dysfunctional in cerebellar degenerative diseases and that an abnormal connectivity within specific cerebello-cortical regions might explain the widespread deficits typically observed in patients. In the present study, the network-based statistics (NBS) approach was used to assess differences in functional connectivity between specific cerebellar and cerebral “nodes” in SCA2 patients. Altered inter-nodal connectivity was found between more posterior regions in the cerebellum and regions in the cerebral cortex clearly related to cognition and emotion. Furthermore, more anterior cerebellar lobules showed altered inter-nodal connectivity with motor and somatosensory cerebral regions. The present data suggest that in SCA2 a cerebellar dysfunction affects long-distance cerebral regions and that the clinical symptoms may be specifically related with connectivity changes between motor and non-motor cerebello-cortical nodes.
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There is growing evidence that the cerebellum is involved in cognition and cognitive development, yet little is known about the developmental relationship between cerebellar structure and cognitive subdomains in children. We used voxel-based morphometry to assess the relationship between cerebellar grey matter (GM) and language, reading, working memory, executive function, and processing speed in 110 individuals aged 8-17 years from the Pediatric Imaging, Neurocognition, and Genetics (PING) Study. Further, we examined the effect of age on the relationships between cerebellar GM and cognition. Higher scores on vocabulary, reading, working memory, and set-shifting were associated with increased GM in the posterior cerebellum (lobules VI–IX), in regions which are typically engaged during cognitive tasks in healthy adults. For reading, working memory, and processing speed, the relationship between cerebellar GM and cognitive performance changed with age in specific cerebellar subregions. As in adults, posterior lobe cerebellar GM was associated with cognitive performance in a pediatric population, and this relationship mirrored the known developmental trajectory of posterior cerebellar GM. These findings provide further evidence that specific regions of the cerebellum support cognition and cognitive development, and suggest that the strength of this relationship depends on developmental stage.
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Background: The natural history of clinical symptoms in the spinocerebellar ataxias (SCA)s has been well characterised. However there is little longitudinal data comparing cognitive changes in the most common SCA subtypes over time. The present study provides a preliminary longitudinal characterisation of the clinical and cognitive profiles in patients with SCA1, SCA2, SCA3, SCA6 and SCA7, with the aim of elucidating the role of the cerebellum in cognition. Methods: 13 patients with different SCAs all caused by CAG repeat expansion (SCA1, n = 2; SCA2, n = 2; SCA3, n = 2; SCA6, n = 4; and SCA7, n = 3) completed a comprehensive battery of cognitive and mood assessments at two time points, a mean of 7.35 years apart. All patients were evaluated clinically using the Scale for the Rating and Assessment of Ataxia (SARA) and the Inventory of Non-Ataxia Signs (INAS). Patients underwent structural MRI imaging at follow-up. Results: Clinical scale scores increased in all patients over time, most prominently in the SCA1 (SARA) and SCA3 (INAS) groups. New impairments on neuropsychological tests were most commonly observed with executive functions, speed, attention, visual memory and Theory of Mind. Results suggest possible differences in cognitive decline in SCA subtypes, with the most rapid cognitive decline observed in the SCA1 patients, and the least in the SCA6 patients, congruent with observed patterns of motor deterioration. Minimal changes in mood were observed, and MRI measures of atrophy did not correlate with cognitive decline. Conclusion: As well as increasing physical impairment, cognitive decline over time appears to be a distinct aspect of the SCA phenotype, in keeping with the cerebellar cognitive-affective syndrome. Our data suggest a trend of cognitive decline that is different for each SCA subtype, and for the majority is related to the severity of cerebellar motor impairment.
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Objectives: The aim of this study was to explore the relationship between cognitive and white matter deterioration in a group of participants with spinocerebellar ataxia type 2 (SCA2). Methods: Fourteen genetically confirmed participants with SCA2 and 14 aged-matched controls participated in the study. Diffusion tensor imaging tract-based spatial statistics were performed to analyze structural white matter integrity. Significant group differences in the mean diffusivity were correlated with SCA2 cognitive deficits. Results: Our analysis revealed higher mean diffusivity in the SCA2 group in cerebellar white matter, medial lemniscus, and middle cerebellar peduncle, among other regions. Cognitive scores correlated with white matter mean diffusivity in the parahippocampal area, inferior frontal and supramarginal gyri and the stria terminalis. Conclusions: Our findings show significant correlations between white matter microstructural damage in key areas affected in SCA2 and cognitive deficits. These findings result in a more comprehensive understanding of the effect of the neurodegenerative process in people with SCA2. (JINS, 2016, 22, 1-6).
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Traditionally the cerebellum has been known for its important role in coordinating motor output. Over the past 15 years numerous studies have indicated that the cerebellum plays a role in a variety of cognitive functions including working memory, language, perceptual functions, and emotion. In addition, recent work suggests that regions of the cerebellum involved in eye movements also play a role in controlling covert visual attention. Here we investigated whether regions of the cerebellum that are not strictly tied to the control of eye movements might also contribute to covert attention. To address this question we examined the effects of circumscribed cerebellar lesions on reflexive covert attention in a group of patients (n = 11) without any gross motor or oculomotor deficits, and compared their performance to a group of age-matched controls (n = 11). Results indicated that the traditional RT advantage for validly cued targets was significantly smaller at the shortest (50 ms) SOA for cerebellar patients compared to controls. Critically, a lesion overlap analysis indicated that this deficit in the rapid deployment of attention was linked to damage in Crus I and Crus II of the lateral cerebellum. Importantly, both cerebellar regions have connections to non-motor regions of the prefrontal and posterior parietal cortices-regions important for controlling visuospatial attention. Together, these data provide converging evidence that both lateral and midline regions of the cerebellum play an important role in the control of reflexive covert visual attention.
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Background: Previous studies of SCA2 have revealed significant degeneration of white matter tracts in cerebellar and cerebral regions. The motor deficit in these patients may be attributable to the degradation of projection fibers associated with the underlying neurodegenerative process. However, this relationship remains unclear. Statistical analysis of diffusion tensor imaging enables an unbiased whole-brain quantitative comparison of the diffusion proprieties of white matter tracts in vivo. Methods: Fourteen genetically confirmed SCA2 patients and aged-matched healthy controls participated in the study. Tract-based spatial statistics were performed to analyze structural white matter damage using two different measurements: fractional anisotropy (FA) and mean diffusivity (MD). Significant diffusion differences were correlated with the patient's ataxia impairment. Results: Our analysis revealed decreased FA mainly in the inferior/middle/superior cerebellar peduncles, the bilateral posterior limb of the internal capsule and the bilateral superior corona radiata. Increases in MD were found mainly in cerebellar white matter, medial lemniscus, and middle cerebellar peduncle, among other regions. Clinical impairment measured with the SARA score correlated with FA in superior parietal white matter and bilateral anterior corona radiata. Correlations with MD were found in cerebellar white matter and the middle cerebellar peduncle. Conclusion: Our findings show significant correlations between diffusion measurements in key areas affected in SCA2 and measures of motor impairment, suggesting a disruption of information flow between motor and sensory-integration areas. These findings result in a more comprehensive view of the clinical impact of the white matter degeneration in SCA2.
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Background: Several neuropathological studies in spinocerebellar ataxia type 2 (SCA2) have revealed significant atrophy of the cerebellum, brainstem, sensorimotor cortex, and several regions in the frontal lobe. However, the impact of the neurodegeneration on the functional integration of the remaining tissue is unknown. To analyze the clinical impact of these functional changes, we correlated the abnormal functional connectivity found in SCA2 patients with their scores in clinical scales. To obtain the functional connectivity changes, we followed two approaches. In one we used areas with significant cerebellar gray matter atrophy as anchor seeds, and in the other we performed a whole-brain data-driven analysis. Methods: Fourteen genetically confirmed SCA2 patients and aged-matched healthy controls participated in the study. Voxel-based morphometry and resting-state functional magnetic resonance imaging (fMRI) were done to analyze structural and functional brain changes. Independent component analysis and dual regression were used for intrinsic network comparison. Significant functional connectivity differences were correlated with the behavioral scores. Results: Seed-based analysis found reduced functional connectivity within the cerebellum and between the cerebellum and frontal/parietal cortices. Cerebellar functional connectivity increases were found with parietal, frontal, and temporal areas. Intrinsic network analysis found a functional decrease in the cerebellar network, and increase in the default-mode and fronto-parietal networks. Further analysis showed significant correlations between clinical scores and the abnormal functional connectivity strength. Conclusion: Our findings show significant correlations between functional connectivity changes in key areas affected in SCA2 and these patients' motor and neuropsychological impairments, adding an important insight to our understanding of the pathophysiology of SCA2. © 2015 International Parkinson and Movement Disorder Society.
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Recent studies have implicated the cerebellum as part of a circuitry that is necessary to modulate higher order and behaviorally relevant information in emotional domains. However, little is known about the relationship between the cerebellum and emotional processing. This study examined cerebellar function specifically in the processing of negative emotions. Transcranial Doppler ultrasonography was performed to detect selective changes in middle cerebral artery flow velocity during emotional stimulation in patients affected by focal or degenerative cerebellar lesions and in matched healthy subjects. Changes in flow velocity during non-emotional (motor and cognitive tasks) and emotional (relaxing and negative stimuli) conditions were recorded. In the present study, we found that during negative emotional task, the hemodynamic pattern of the cerebellar patients was significantly different to that of controls. Indeed, whereas relaxing stimuli did not elicit an increase in mean flow velocity in any group, negative stimuli increased the mean flow velocity in the right compared with left middle cerebral artery only in the control group. The patterns by which mean flow velocity increased during the motor and cognitive tasks were similar within patients and controls. These findings support that the cerebellum is part of a network that gives meaning to external stimuli, and this particular involvement in processing negative emotional stimuli corroborates earlier phylogenetic hypotheses, for which the cerebellum is part of an older circuit in which negative emotions are crucial for survival and prepare the organism for rapid defense.
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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.
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Spinocerebellar Ataxia Type 2 (SCA2) is a genetic disorder causing cerebellar degeneration that result in motor and cognitive alterations. Voxel-based Morphometry (VBM) analyses have found neurodegenerative patterns associated to SCA2, but they show some discrepancies. Moreover, behavioral deficits related to non-cerebellar functions are scarcely discussed in those reports. In this work we use behavioral and cognitive tests and VBM to identify and confirm cognitive and gray matter alterations in SCA2 patients compared with control subjects. Also, we discuss the cerebellar and non-cerebellar functions affected by this disease. Our results confirmed gray matter reduction in the cerebellar vermis, pons, insular, frontal, parietal and temporal cortices. However, our analysis also found unreported loss of gray matter in the parahippocampal gyrus bilaterally. Motor performance test ratings correlated with total gray and white matter reductions, but executive performance and clinical features such as CAG repetitions and disease progression did not show any correlation. This pattern of cerebellar and non-cerebellar morphological alterations associated with SCA2 has to be considered to fully understand the motor and non-motor deficits that include language production and comprehension and some social skills changes that occur in these patients.
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Cerebellar research has focused principally on adult motor function. However, the cerebellum also maintains abundant connections with nonmotor brain regions throughout postnatal life. Here we review evidence that the cerebellum may guide the maturation of remote nonmotor neural circuitry and influence cognitive development, with a focus on its relationship with autism. Specific cerebellar zones influence neocortical substrates for social interaction, and we propose that sensitive-period disruption of such internal brain communication can account for autism's key features.
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Computational theories propose that attention modulates the topographical landscape of spatial 'priority' maps in regions of the visual cortex so that the location of an important object is associated with higher activation levels. Although studies of single-unit recordings have demonstrated attention-related increases in the gain of neural responses and changes in the size of spatial receptive fields, the net effect of these modulations on the topography of region-level priority maps has not been investigated. Here we used functional magnetic resonance imaging and a multivariate encoding model to reconstruct spatial representations of attended and ignored stimuli using activation patterns across entire visual areas. These reconstructed spatial representations reveal the influence of attention on the amplitude and size of stimulus representations within putative priority maps across the visual hierarchy. Our results suggest that attention increases the amplitude of stimulus representations in these spatial maps, particularly in higher visual areas, but does not substantively change their size.
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The autosomal dominant cerebellar ataxias, also known as spinocerebellar ataxias (SCA), are characterized by cerebellar degeneration and by their afferent and efferent connections. Currently, at least 31 types of SCA are described, among which a subset, comprising types 1, 2, 3, 6, 7, 17 of the disease, is distinguished due to sharing the same form of mutation involving the repetition of the series of CAG triplets, known as polyglutamine diseases (SCApolyQ). Through a systematic literature review using the Pubmed, PsycoINFO, LILACS and SciELO databases and the keywords Spinocerebellar Ataxia in association with the words neuropsychiatric, psychological, cognitive impairment(s) and psychiatric comorbidities this study aimed to identify the possible associations between SCApolyQ and neuropsychological and psychiatric symptoms/disorders. A greater presence of symptoms of depression and anxiety was evidenced, as well as the existence of cognitive impairments in the patients with SCApolyQ when compared with the general population, with important differences in the profile of these impairments among the types of SCA. It was observed that the findings, in general, indicated greater impairment in the executive functions, verbal fluency and verbal memory and that there was a higher concentration of studies for SCA2 and SCA3. However, there is a need for a greater number of studies using a more homogeneous methodology, which perform direct comparisons between the types of ataxias and that explore some of the still little evaluated neuropsychological functions and the different psychiatric disorders in their amplitude.
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Insights from both lesion and neuroimaging studies increasingly substantiate the view that the human cerebellum not only serves motor control but also supports various cognitive processes. Higher cognitive functions like working memory or executive control have been associated with the phylogenetically younger parts of the cerebellum, crus I and crus II. Functional connectivity studies corroborate this notion as activation of the cerebellum correlates with activity in numerous areas of the cerebral cortex. Moreover, these cerebrocerebellar loops were shown to be topographically organized. We used an attention-to-motion paradigm to elaborate on the effective connectivity of cerebellar crus I during visual attention. Psychophysiological interaction analyses demonstrated enhanced connectivity of the cerebellum--during attention--with dorsal visual stream regions including posterior parietal cortex (PPC) and left secondary visual cortex (V5). Dynamic causal modeling revealed a modulation of the connections from V5 to PPC and from crus I to V5 by attention. Remarkably, the influence which V5 exerted on PPC was reduced during attention, resulting in a suppression of the sensitivity of PPC to bottom-up information. Moreover, the sensitivity of V5 populations to inputs from crus I was increased under attention. This might underscore the presumed role of the cerebellum as a state estimator that provides hierarchically lower regions (V5) with top-down predictions, which in turn might be based on endogenous inputs from PPC to the cerebellum. These results are in line with formulations of attention in predictive coding, where attention increases the precision or sensitivity of hierarchically lower neuronal populations that may encode prediction error.
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The cerebellar role in non-motor functions is supported by the clinical finding that lesions confined to cerebellum produce the cerebellar cognitive affective syndrome. Nevertheless, there is no consensus regarding the overall cerebellar contribution to cognition. Among other reasons, this deficiency might be attributed to the small sample sizes and narrow breadths of existing studies on lesions in cerebellar patients, which have focused primarily on a single cognitive domain. The aim of this study was to examine the expression of cerebellar cognitive affective syndrome with regard to lesion topography in a large group of subjects with cerebellar damage. We retrospectively analysed charts from patients in the Ataxia Lab of Santa Lucia Foundation between 1997 and 2007. Of 223 charts, 156 were included in the study, focusing on the importance of the cerebellum in cognition and the relevance of lesion topography in defining the cognitive domains that have been affected. Vascular topography and the involvement of deep cerebellar nuclei were the chief factors that determined the cognitive profile. Of the various cognitive domains, the ability to sequence was the most adversely affected in nearly all subjects, supporting the hypothesis that sequencing is a basic cerebellar operation.
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In recent decades there has been a significant increase in the number of articles that have drawn attention to the possible importance of the role of the cerebellum in non-motor functions. Schmahmann and Sherman, for example, have described the cognitive, behavioural and emotional pattern of what has been called cerebellar cognitive affective syndrome. A central aspect of this disorder is the dysregulation of affect that occurs when lesions involve what has been called the limbic cerebellum (mainly the vermis). A non-systematic review of the most important literature on the role of the cerebellum in emotional and behavioural regulation was carried out. Two lines of analysis were followed. The first of them was the study of the psycho-pathological symptoms or neuropsychiatric disorders presented by patients suffering from different cerebellar pathologies ranging from congenital pathologies such as agenesis of the cerebellum, dysplasia or hypoplasia to other acquired diseases like tumours in the posterior fossa, cerebellitis or superficial siderosis. In such cases it has been seen that when the cerebellar vermis is compromised, patients display disorders affecting their behaviour and emotions, and psychiatric pathologies are more frequent. In the second line, we analysed the role played by the cerebellum in different psycho-pathological disorders in which the structure of the cerebellum was found to be altered. Although not universal, these alterations were consistent, since they involve the cerebellar vermis. Although the body of evidence continues to grow, a critical review of the scientific literature leads us to reflect on evolution in the study of the cerebral substrate underlying the cognitive functions and the evolution undergone by this study.
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Over the last decade, studies have implicated the cerebellum not only in motor functioning, but also in cognition and social cognition. Although some aspects of cognition have been explored in the five most common forms of Spinocerebellar Ataxia (SCA), social cognition in these patients has rarely been examined. The present study provides a preliminary characterisation of the severity of cognitive and social cognitive impairments in patients with SCA2, SCA1 and SCA7 using an identical battery to the one previously used in SCA3 and SCA6 patients for comparison. The cognitive profiles of SCA1 and SCA7 patients were comparable to that of SCA6 patients; SCA1 patients had relatively intact profiles, while SCA7 patients demonstrated only some selective deficits. In contrast, SCA2 patients showed the greatest impairments, similarly to SCA3 patients. On tests of social cognition, SCA2 and SCA7 patients were impaired on a task of emotion attribution, whereas one SCA1 patient had a Theory of Mind deficit, which has also been documented in SCA3 and SCA6. We provide preliminary evidence that the neuropsychological profiles of SCA patients correspond well with the severity of pathological and clinical features. Moreover, these patients may also have social cognition impairments. Overall, we suggest that there is a degree of heterogeneity in the types of cognitive and social cognitive impairments in SCA patients.
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Over the past 30 years, cumulative evidence has indicated that cerebellar function extends beyond sensorimotor control. This view has emerged from studies of neuroanatomy, neuroimaging, neuropsychology, and brain stimulation, with the results implicating the cerebellum in domains as diverse as attention, language, executive function, and social cognition. Although the literature provides sophisticated models of how the cerebellum helps refine movements, it remains unclear how the core mechanisms of these models can be applied when considering a broader conceptualization of cerebellar function. In light of recent multidisciplinary findings, we examine how two key concepts that have been suggested as general computational principles of cerebellar function- prediction and error-based learning- might be relevant in the operation of cognitive cerebro-cerebellar loops.
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The human brain contains approximately 60 billion cerebellar granule cells, which outnumber all other brain neurons combined. Classical theories posit that a large, diverse population of granule cells allows for highly detailed representations of sensorimotor context, enabling downstream Purkinje cells to sense fine contextual changes. Although evidence suggests a role for the cerebellum in cognition, granule cells are known to encode only sensory and motor context. Here, using two-photon calcium imaging in behaving mice, we show that granule cells convey information about the expectation of reward. Mice initiated voluntary forelimb movements for delayed sugar-water reward. Some granule cells responded preferentially to reward or reward omission, whereas others selectively encoded reward anticipation. Reward responses were not restricted to forelimb movement, as a Pavlovian task evoked similar responses. Compared to predictable rewards, unexpected rewards elicited markedly different granule cell activity despite identical stimuli and licking responses. In both tasks, reward signals were widespread throughout multiple cerebellar lobules. Tracking the same granule cells over several days of learning revealed that cells with reward-anticipating responses emerged from those that responded at the start of learning to reward delivery, whereas reward-omission responses grew stronger as learning progressed. The discovery of predictive, non-sensorimotor encoding in granule cells is a major departure from the current understanding of these neurons and markedly enriches the contextual information available to postsynaptic Purkinje cells, with important implications for cognitive processing in the cerebellum.
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In recent years the cerebellum has been attributed a more important role in higher-level functions than previously believed. We examined a cohort of patients suffering from cerebellar atrophy resulting in ataxia, with two main objectives: first to investigate which regions of the cerebrum were affected by the cerebellar degeneration, and second to assess whether diffusion magnetic resonance imaging (dMRI) metrics within the medial (MCP) and superior cerebellar peduncle (SCP)-namely fractional anisotropy (FA) and radial diffusivity (RD)-could be used as a biomarker in patients with this condition. Structural and dMRI data of seven patients with cerebellar atrophy (2 with spinocerebellar atrophy type 2, 1 with Friedreich’s ataxia, 4 with idiopathic cerebellar ataxia) and no visible cortical lesions or cortical atrophy were investigated with Freesurfer and voxel-based morphometry (VBM) of gray matter (GM) as well as MCP and SCP FA maps. Correlations of MCP and SCP mean FA with ataxia scores and subscores were also evaluated. Freesurfer showed that patients had significantly reduced volume of the thalamus, ventral diencephalon and pallidum. VBM also demonstrated significantly lower local GM volumes in patients, notably in the head of the caudate nucleus, posterior cingulate gyrus and orbitofrontal cortex bilaterally, as well as in Broca’s area in the left hemisphere, and a significant increase in RD in the MCP and SCP of both hemispheres. A significant correlation was found between MCP mean FA and total ataxia score (R=−0.7, p=0.03), and subscores for kinetic functions (R=−0.74, p=0.03) and oculomotor disorders (R=−0.70, p=0.04). The regions of the cerebrum found to have significantly lower local GM volumes have been described to be involved in higher-level cerebellar functions such as initiation of voluntary movements, emotional control, memory retrieval and general cognition. Our findings corroborate recent research pointing to a more extensive corticocerebellar system than previously thought. The significant difference in the MCP and SCP dMRI metrics between patients and controls as well as the significant correlation with ataxia total score and subscores support the use of dMRI metrics as an imaging biomarker for cerebellar degeneration and ataxia. © 2016, CIC Edizioni Internazionali s.r.l. All rights reserved.
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Detailed mapping of clinical dysfunctions to the cerebellar lobules in disease populations is necessary to establish the functional significance of lobules implicated in cognitive and motor functions in normal subjects. This study constitutes the first quantitative examination of the lobular correlates of a broad range of cognitive and motor phenomena in cerebellar disease. We analysed cross-sectional data from 72 cases with cerebellar disease and 36 controls without cerebellar disease. Cerebellar lobule volumes were derived from a graph-cut based segmentation algorithm. Sparse partial least squares, a variable selection approach, was used to identify lobules associated with motor function, language, executive function, memory, verbal learning, perceptual organization and visuomotor coordination. Motor dysfunctions were chiefly associated with the anterior lobe and posterior lobule HVI. Confrontation naming, noun fluency, recognition, and perceptual organization did not have cerebellar associations. Verb and phonemic fluency, working memory, cognitive flexibility, immediate and delayed recall, verbal learning, and visuomotor coordination were variably associated with HVI, Crus I, Crus II, HVII B and/or HIX. Immediate and delayed recall also showed associations with the anterior lobe. These findings provide preliminary anatomical evidence for a functional topography of the cerebellum first defined in task-based functional magnetic resonance imaging studies of normal subjects and support the hypotheses that (i) cerebellar efferents target frontal lobe neurons involved in forming action representations and new search strategies; (ii) there is greater involvement of the cerebellum when immediate recall tasks involve more complex verbal stimuli (e.g. longer words versus digits); and (iii) it is involved in spontaneous retrieval of long-term memory. More generally, they provide an anatomical background for studies that seek the mechanisms by which cognitive and motor dysfunctions arise from cerebellar degeneration. Beyond replicating these findings, future research should employ experimental tasks to probe the integrity of specific functions in cerebellar disease, and new imaging methods to quantitatively map atrophy across the cerebellum.
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Unlabelled: The "dorsal attention network" or "frontoparietal network" refers to a network of cortical regions that support sustained attention and working memory. Recent work has demonstrated that cortical nodes of the dorsal attention network possess intrinsic functional connections with a region in ventral cerebellum, in the vicinity of lobules VII/VIII. Here, we performed a series of task-based and resting-state fMRI experiments to investigate cerebellar participation in the dorsal attention network in humans. We observed that visual working memory and visual attention tasks robustly recruit cerebellar lobules VIIb and VIIIa, in addition to canonical cortical dorsal attention network regions. Across the cerebellum, resting-state functional connectivity with the cortical dorsal attention network strongly predicted the level of activation produced by attention and working memory tasks. Critically, cerebellar voxels that were most strongly connected with the dorsal attention network selectively exhibited load-dependent activity, a hallmark of the neural structures that support visual working memory. Finally, we examined intrinsic functional connectivity between task-responsive portions of cerebellar lobules VIIb/VIIIa and cortex. Cerebellum-to-cortex functional connectivity strongly predicted the pattern of cortical activation during task performance. Moreover, resting-state connectivity patterns revealed that cerebellar lobules VIIb/VIIIa group with cortical nodes of the dorsal attention network. This evidence leads us to conclude that the conceptualization of the dorsal attention network should be expanded to include cerebellar lobules VIIb/VIIIa. Significance statement: The functional participation of cerebellar structures in nonmotor cortical networks remains poorly understood and is highly understudied, despite the fact that the cerebellum possesses many more neurons than the cerebral cortex. Although visual attention paradigms have been reported to activate cerebellum, many researchers have largely dismissed the possibility of a cerebellar contribution to attention in favor of a motor explanation, namely, eye movements. The present study demonstrates that a cerebellar subdivision (mainly lobules VIIb/VIIIa), which exhibits strong intrinsic functional connectivity with the cortical dorsal attention network, also closely mirrors a myriad of cortical dorsal attention network responses to visual attention and working memory tasks. This evidence strongly supports a reconceptualization of the dorsal attention network to include cerebellar lobules VIIb/VIIIa.
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Ronconi L.*, Casartelli L.*, Carna S., Molteni M., Arrigoni F., Borgatti R. *CO-FIRST AUTHORSHIP ABSTRACT In the last two decades, an intriguing shift in the understanding of the cerebellum has led to consider the non-motor functions of this structure. Although various aspects of perceptual and sensory processing have been linked to the cerebellar activity, whether the cerebellum is essential for binding information from different sensory modalities remains uninvestigated. Multisensory integration (MSI) appears very early in the ontogenesis and is critical in several perceptual, cognitive and social domains. For the first time, we investigated MSI in a rare case of cerebellar agenesis without any other associated brain malformations. To this aim, we measured reaction times (RTs) after the presentation of visual, auditory and audiovisual stimuli. A group of neurotypical age-matched individuals was used as controls. Although we observed the typical advantage of the auditory modality relative to the visual modality in our patient, a clear impairment in MSI was found. Beyond the obvious prudence necessary for inferring definitive conclusions from this single-case picture, this finding is of interest in the light of reduced MSI abilities reported in several neurodevelopmental and psychiatric disorders – such as autism, dyslexia, and schizophrenia – in which the cerebellum has been implicated.
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Clinical, neuroanatomic, neurobehavioral, and functional brain-imaging studies suggest a role for the cerebellum in cognitive functions, including attention. However, the cerebellum has not been systematically studied in attention-deficit hyperactivity disorder (ADHD). We quantified the cerebellar and vermal volumes, and the midsagittal areas of three vermal regions, from MRIs of 46 right-handed boys with ADHD and 47 matched healthy controls. Vermal volume was significantly less in the boys with ADHD. This reduction involved mainly the posterior inferior lobe (lobules VIII to X) but not the posterior superior lobe (lobules VI to VII). These results remained significant even after adjustment for brain volume and IQ. A cerebello-thalamo-prefrontal circuit dysfunction may subserve the motor control, inhibition, and executive function deficits encountered in ADHD.
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The ability of DTI to track the progression of microstructural damage in patients with inherited ataxias has not been explored so far. We performed a longitudinal DTI study in patients with spinocerebellar ataxia type 2. Ten patients with spinocerebellar ataxia type 2 and 16 healthy age-matched controls were examined twice with DTI (mean time between scans, 3.6 years [patients] and 3.3 years [controls]) on the same 1.5T MR scanner. Using tract-based spatial statistics, we analyzed changes in DTI-derived indices: mean diffusivity, axial diffusivity, radial diffusivity, fractional anisotropy, and mode of anisotropy. At baseline, the patients with spinocerebellar ataxia type 2, as compared with controls, showed numerous WM tracts with significantly increased mean diffusivity, axial diffusivity, and radial diffusivity and decreased fractional anisotropy and mode of anisotropy in the brain stem, cerebellar peduncles, cerebellum, cerebral hemisphere WM, corpus callosum, and thalami. Longitudinal analysis revealed changes in axial diffusivity and mode of anisotropy in patients with spinocerebellar ataxia type 2 that were significantly different than those in the controls. In patients with spinocerebellar ataxia type 2, axial diffusivity was increased in WM tracts of the right cerebral hemisphere and the corpus callosum, and the mode of anisotropy was extensively decreased in hemispheric cerebral WM, corpus callosum, internal capsules, cerebral peduncles, pons and left cerebellar peduncles, and WM of the left paramedian vermis. There was no correlation between the progression of changes in DTI-derived indices and clinical deterioration. DTI can reveal the progression of microstructural damage of WM fibers in the brains of patients with spinocerebellar ataxia type 2, and mode of anisotropy seems particularly sensitive to such changes. These results support the potential of DTI-derived indices as biomarkers of disease progression. © 2015 American Society of Neuroradiology.
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It has been demonstrated that motor learning is supported by the cerebellum and the cerebro-cerebellar interaction. Response inhibition involves motor responses and the higher-order inhibition that controls the motor responses. In this functional MRI study, we measured the cerebro-cerebellar interaction during response inhibition in two separate days of task performance, and detected the changes in the interaction following performance improvement. Behaviorally, performance improved in the second day, compared to the first day. The psycho-physiological interaction (PPI) analysis revealed the interaction decrease from the right inferior frontal cortex (rIFC) to the cerebellum (lobule VII or VI). It was also revealed that the interaction increased from the same cerebellar region to the primary motor area. These results suggest the involvement of the cerebellum in response inhibition, and raise the possibility that the performance improvement was supported by the changes in the cerebro-cerebellar interaction.
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The role of the cerebellum in cognition, both in healthy subjects and in patients with cerebellar diseases, is debated. Neuropsychological studies in spinocerebellar ataxia type 1 (SCA1) and type 2 (SCA2) demonstrated impairments in executive functions, verbal memory, and visuospatial performances, but prospective evaluations are not available. Our aims were to assess progression of cognitive and psychiatric functions in patients with SCA1 and SCA2 in a longitudinal study. We evaluated at baseline 20 patients with SCA1, 22 patients with SCA2 and 17 matched controls. Two subgroups of patients (9 SCA1, 11 SCA2) were re-evaluated after 2 years. We tested cognitive functions (Mini Mental State Examination, digit span, Corsi span, verbal memory, attentional matrices, modified Wisconsin Card Sorting Test, Raven Progressive Matrices, Benton test, phonemic and semantic fluency), psychiatric status (Scales for Assessment of Negative and Positive Symptoms, Hamilton Depression and Anxiety Scales), neurological conditions (Scale for Assessment and Rating of Ataxia), and functional abilities (Unified Huntington Disease Rating Scale-part IV). At baseline, SCA1 and SCA2 patients had significant deficits compared to controls, mainly in executive functions (phonemic and semantic fluencies, attentional matrices); SCA2 showed further impairment in visuospatial and visuoperceptive tests (Raven matrices, Benton test, Corsi span). Both SCA groups had higher depression and negative symptoms, particularly apathy, compared to controls. After 2 years, motor and functional disability worsened, while only attentive performances deteriorated in SCA2. This longitudinal study showed dissociation in progression of motor disability and cognitive impairment, suggesting that in SCA1 and SCA2 motor and cognitive functions might be involved with different progression rates.
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Abstract In a previous study, we found that patients with damage to the neocerebellum were significantly impaired in the ability to rapidly shift their attention between ongoing sequences of auditory and visual stimuli (Akshoomoff & Courchesne, 1992). In the present study, young patients with damage to the neoccrebelluni were found to be impaired in rapidly shifting their mention between visual stimuli that occurred within a single location. Event-related potentials recorded during the shifting attention experiment suggested that this reflects a deficit in the. covert ability to selectively activate and deactivate attention. These results lend Further support to the hypothesis that the neocerebellum plays a role in the ability to rapidly shift attention.
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Despite the involvement of cerebellar ataxia in a large variety of conditions and its frequent association with other neurological symptoms, the quantification of the specific core of the cerebellar syndrome is possible and useful in Neurology. Recent studies have shown that cerebellar ataxia might be sensitive to various types of pharmacological agents, but the scales used for assessment were all different. With the long-term goal of double-blind controlled trials —multicentric and international — an ad hoc Committee of the World Federation of Neurology has worked to propose a one-hundred-point semi-quantitative International Cooperative Ataxia Rating Scale (ICARS). The scale proposed involves a compartimentalized quantification of postural and stance disorders, limb ataxia, dysarthria and oculomotor disorders, in order that a subscore concerning these symptoms may be separately studied. The weight of each symptomatologic compartment has been carefully designed. The members of the Committee agreed upon precise definitions of the tests, to minimize interobserver variations. The validation of this scale is in progress. © 1997 Elsevier Science B.V. All rights reserved.
Article
Background: The ability to distinguish sensory signals that register unexpected events (exafference) from those generated by voluntary actions (reafference) during self-motion is essential for accurate perception and behavior. The cerebellum is most commonly considered in relation to its contributions to the fine tuning of motor commands and sensorimotor calibration required for motor learning. During unexpected motion, however, the sensory prediction errors that drive motor learning potentially provide a neural basis for the computation underlying the distinction between reafference and exafference. Results: Recording from monkeys during voluntary and applied self-motion, we demonstrate that individual cerebellar output neurons encode an explicit and selective representation of unexpected self-motion by means of an elegant computation that cancels the reafferent sensory effects of self-generated movements. During voluntary self-motion, the sensory responses of neurons that robustly encode unexpected movement are canceled. Neurons with vestibular and proprioceptive responses to applied head and body movements are unresponsive when the same motion is self-generated. When sensory reafference and exafference are experienced simultaneously, individual neurons provide a precise estimate of the detailed time course of exafference. Conclusions: These results provide an explicit solution to the longstanding problem of understanding mechanisms by which the brain anticipates the sensory consequences of our voluntary actions. Specifically, by revealing a striking computation of a sensory prediction error signal that effectively distinguishes between the sensory consequences of self-generated and externally produced actions, our findings overturn the conventional thinking that the sensory errors coded by the cerebellum principally contribute to the fine tuning of motor activity required for motor learning.
Article
The cerebellum is believed to play an essential role in a variety of motor and cognitive functions through reciprocal interaction with the cerebral cortex. Recent findings suggest that cerebellar involvement in the network specialized for visual body motion processing may be mediated through interaction with the right superior temporal sulcus (STS). Yet, the underlying pattern of structural connectivity between the STS and the cerebellum remains unidentified. In the present work, diffusion tensor imaging analysis on seeds derived from functional magnetic resonance imaging during a task on point-light biological motion perception uncovers a structural pathway between the right posterior STS and the left cerebellar lobule Crus I. The findings suggest existence of a structural loop underpinning bidirectional communication between the STS and cerebellum. This connection might also be of potential value for other visual social abilities.
Article
A group of sixty-six adult subjects was given the task of producing as many words as possible beginning with specified letters of the alphabet. The number of words produced during a period of 60 sec correlated highly both with a frequency count derived from the Thorndike-Lorge norms and with estimates derived from the dictionary of the number of words in the English language beginning with each letter. In a second experiment, eight letters representing three levels of difficulty as found in normal subjects were given to thirty brain-damaged and thirty hospitalized control patients. Results in terms of verbal productivity indicated that, for patients of high intelligence, difficult letters (i.e. J and U) showed the greatest discrimination. On the other hand, for patients of low intelligence, easy letters (i.e. F, S, P and T) were more effective in differentiating the brain-damage and control groups. The findings also indicated that difficult letters may be particularly effective in distinguishing between patients with right and left hemisphere damage. An analysis of order of presentation indicated that practice and fatigue effects were not related to verbal fluency when as many as eight letters were administered. It is suggested that the addition of difficult letters to standard word fluency tests may yield more precise discriminations between brain-damaged and control patients when overall level of intellectual functioning is taken into account.
Article
The cerebellum is one of the well-known targets of the pathological processes underlying spinocerebellar ataxia type 2 (SCA2) and type 3 (SCA3). Despite its pivotal role for the clinical pictures of these polyglutamine ataxias, no pathoanatomical studies of serial tissue sections through the cerebellum have been performed in SCA2 and SCA3 so far. Detailed pathoanatomical data are an important prerequisite for the identification of the initial events of the underlying disease processes of SCA2 and SCA3 and the reconstruction of its spread through the brain. In the present study, we performed a pathoanatomical investigation of serial thick tissue sections through the cerebellum of clinically diagnosed and genetically confirmed SCA2 and SCA3 patients. This study demonstrates that the cerebellar Purkinje cell layer and all four deep cerebellar nuclei consistently undergo considerable neuronal loss in SCA2 and SCA3. These cerebellar findings contribute substantially to the pathogenesis of clinical symptoms (i.e., dysarthria, intention tremor, oculomotor dysfunctions) of SCA2 and SCA3 patients and may facilitate the identification of the initial pathological alterations of the pathological processes of SCA2 and SCA3 and reconstruction of its spread through the brain.
Article
The cerebellum is thought to be engaged not only in motor control, but also in the neural network dedicated to visual processing of body motion. However, the pattern of connectivity within this network, in particular, between the cortical circuitry for observation of others' actions and the cerebellum remains largely unknown. By combining functional magnetic resonance imaging (fMRI) with functional connectivity analysis and dynamic causal modelling (DCM), we assessed cerebro-cerebellar connectivity during a visual perceptual task with point-light displays depicting human locomotion. In the left lateral cerebellum, regions in the lobules Crus I and VIIB exhibited increased fMRI response to biological motion. The outcome of the connectivity analyses delivered the first evidence for reciprocal communication between the left lateral cerebellum and the right posterior superior temporal sulcus (STS). Through communication with the right posterior STS that is a key node not only for biological motion perception but also for social interaction and visual tasks on theory of mind, the left cerebellum might be involved in a wide range of social cognitive functions.
Article
A subtype-specific impairment of cognitive functions in spinocerebellar ataxia (SCA) patients is still debated. Thirty-two SCA patients (SCA1, 6; SC2, 3; SCA3, 15; SCA6, 8) and 14 matched healthy controls underwent neuropsychological evaluation testing attention, executive functions, episodic and semantic memory, and motor coordination. Severity of ataxia was assessed with the Scale for the Assessment and Rating of Ataxia (SARA), nonataxia symptoms with the Inventory of Non-Ataxia Symptoms. Depressive symptoms were evaluated with the Beck Depression Inventory. The SARA scores of our SCA patients (range 1-19.5) indicated an overall moderate ataxia, most pronounced in SCA6 and SCA1. Mean number of nonataxia symptoms (range 0-2.2) were most distinct in SCA1 and nearly absent in SCA6. SCA1 performed poorer than controls in 33% of all cognitive test parameters, followed by SCA2, SCA3, and SCA6 patients (17%). SCA 1-3 patients presented mainly attentional and executive dysfunctions while semantic and episodic memory functions were preserved. Attentional and executive functions were partly correlated with ataxia severity and fine motor coordination. All patients exhibited mildly depressed mood. Motor and dominant hand functions were more predictive for depressed mood than cognitive measures or overall ataxia. Besides motor impairments in all patients, SCA patients with extracerebellar pathology (SCA 1-3) were characterized by poor frontal attentional and executive dysfunction while mild cognitive impairments in predominantly cerebellar SCA6 patients appeared to reflect mainly cerebellar dysfunction. Regarding the everyday relevance of symptoms, (dominant) motor hand functioning emerged as a marker for the patient's mood.
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Short title on half-title page: Memory and the medial temporal region of the brain. Thesis (Ph. D.)--McGill University, 1972. Includes bibliographical references (leaves 69-78). Microfilm of typescript.
Article
Anatomical, experimental, functional neuroimaging, and clinical data implicate the importance of corticocerebellar interactions in many nonmotor domains, such as sensory, cognitive, emotional, and affective processing. The modular organization and multifarious domains of activity suggest that cerebellar functional specificity has to be searched in a processing modality that is applicable to various contexts. One theory, among many, proposes that "sequence in" of sensory information is critical to understand cerebellar functioning. Here, we aimed at reinterpreting previous findings according to the cerebellar "sequence detection" theory. Spatial function, language, verbal memory, and sequence processing all are domains that are reported impaired after cerebellar damage. Reviewing data that have focused on sequential information processing highlighted the importance of the cerebellum in detecting patterns of incoming stimuli or in central circuit activities. Cerebellar sequence processing should be considered within the known organization of cerebellocortical connections. Within this framework, depending on the involved loop, cerebellar damage can provoke different functional impairments such as defective processing of sensorial stimuli sequences; defective sequential detection error-based learning; defective comparison between incoming sensory patterns and internal modules, and so on.
Article
The functional organization of the cerebellum is reflected in large part by the unique afferent and efferent connectivity of the individual cerebellar lobules. This functional diversity on a relatively small spatial scale makes accurate localization methods for human functional imaging and anatomical patient-based research indispensable. Here we present a probabilistic atlas of the cerebellar lobules in the anatomical space defined by the MNI152 template. We separately masked the lobules on T1-weighted MRI scans (1 mm isotropic resolution) of 20 healthy young participants (10 male, 10 female, average age 23.7 yrs). These cerebella were then aligned to the standard or non-linear version of the whole-brain MNI152 template using a number of commonly used normalization algorithms, or to a previously published cerebellum-only template (Diedrichsen, J., 2006. A spatially unbiased atlas template of the human cerebellum. NeuroImage 33, 127-138.). The resulting average overlap was higher for the cerebellum-only template than for any of the whole-brain normalization methods. The probabilistic maps allow for the valid assignment of functional activations to specific cerebellar lobules, while providing a quantitative measure of the uncertainty of such assignments. Furthermore, maximum probability maps derived from these atlases can be used to define regions of interest (ROIs) in functional neuroimaging and neuroanatomical research. The atlas, made freely available online, is compatible with a number of widely used analysis packages.