Article

Quantification of gray matter changes in the cerebral cortex after isolated cerebellar damage: A voxel-based morphometry study

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Abstract

There is growing evidence based on behavioral and functional imaging studies about the cerebellar involvement in the modulation of cognitive functions. However, it still remains to be clarified how the cerebellum interacts with brain regions sub-serving different cognitive domains. In this study we used magnetic resonance imaging (MRI) and voxel based morphometry (VBM) to investigate changes of cerebral gray matter (GM) density in 15 patients with a focal cerebellar damage (CD) compared to 15 healthy controls. T2-weighted scans and T1-weighted volumes were collected from each subject. With the exception of the cerebellar lesion, none of the patients showed any additional brain MRI abnormality. T1-volumes were analyzed by voxel-based morphometry. Consistent with their neuropsychological abnormalities, patients with right-CD compared to controls showed a reduction of GM density mainly involving the left frontal, parietal and temporal lobes. Conversely, patients with left-CD did not show any significant neuropsychological or cerebral GM abnormality. The present study indicates that specific GM changes may be detected in patients with isolated CD and cognitive dysfunction. We discuss the findings in terms of cerebellar influence on the neuronal networks involved in higher level functions of the association cortex.

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... Specifically, cerebellar cognitive impairment has been linked to a functional alteration of cerebellocerebral interaction (Broich et al., 1987, Clausi et al., 2009, Komaba et al., 2000. Moreover, it has been recently shown that cerebellar dysfunctions may affect spatially-separated regions of the brain and that cerebellar cognitive impairment could be related to abnormal functional connectivity (FC) patterns within specific cerebello-cortical networks (Olivito et al., 2017b). ...
... The participation of the cerebellum in several cognitive functions, also including verbal memory (Grasby et al., 1993;Andreasen et al., 1995), and visuo-spatial abilities (Parsons and Fox, 1997) is now widely accepted. Association between specific cerebellar regions and cognitive functions was first derived from functional MRI studies in healthy subjects (Stoodley and Schmahmann, 2009), and further supported by behavioral Schmahmann, 1998) and neuroimaging studies Stoodley et al., 2016;Clausi et al., 2009) in cerebellar damaged patients that showed a relation between cerebellar structural alterations and cognitive deficits. The hypothesis is that, as a consequence of the isolated cerebellar damage, the neurons of the connected cerebral regions undergo an alteration of the synaptic inputs that they normally receive from the cerebellum and this may induce a structural reorganization of these cortical neurons that also results in functional impairment (Clausi et al., 2009). ...
... Association between specific cerebellar regions and cognitive functions was first derived from functional MRI studies in healthy subjects (Stoodley and Schmahmann, 2009), and further supported by behavioral Schmahmann, 1998) and neuroimaging studies Stoodley et al., 2016;Clausi et al., 2009) in cerebellar damaged patients that showed a relation between cerebellar structural alterations and cognitive deficits. The hypothesis is that, as a consequence of the isolated cerebellar damage, the neurons of the connected cerebral regions undergo an alteration of the synaptic inputs that they normally receive from the cerebellum and this may induce a structural reorganization of these cortical neurons that also results in functional impairment (Clausi et al., 2009). ...
Article
Alzheimer's disease (AD) is a chronic neurodegenerative disorder characterized by specific patterns of gray and white matter damage and cognitive/behavioral manifestations. The cerebellum has also been implicated in the pathophysiology of AD. Because the cerebellum is known to have strong functional connectivity (FC) with associative cerebral cortex regions, it is possible to hypothesize that it is incorporated into intrinsic FC networks relevant to cognitive manifestation of AD. In the present study, the cerebellar dentate nucleus, the largest cerebellar nucleus and the major output channel to the cerebral cortex, was chosen as the region of interest to test potential cerebellocerebral FC alterations and correlations with patients' memory impairment in a group of patients with AD. Compared to controls, patients with AD showed an increase in FC between the dentate nucleus and regions of the lateral temporal lobe. This study demonstrates that lower memory performances in AD may be related to altered FC within specific cerebellocortical functional modules, thus suggesting the cerebellar contribution to AD pathophysiology and typical memory dysfunctions.
... Functional studies with healthy subjects also support the anatomical evidence of functionally related parallel cortico-cerebellar loops [11]. Based on recent evidence from a Voxel Based Morphometry (VBM) study, the clinical alterations consequent to a focal cerebellar lesion are associated with specific structural modifications in cerebello-related areas of the cerebral cortex [12]. The interruption of cerebellothalamo-cortical pathways has been reported as the mechanism responsible for crossed cerebello-cerebral diaschisis (CCCD) [13][14][15]. ...
... Thus, our findings indicate prevalent bilateral myelin damage with relative axonal sparing. Focal cerebellar lesions have been described to result in impaired higher cognitive functions, associated with structural modifications in cerebral cortex regions functionally linked to the cerebellar lesioned areas [6,12]. Specifically, a focal cerebellar lesion has been described to result in a functional impairment of the contralateral cerebral cortex (crossed cerebello-cerebral diaschisis) [14][15][45][46], consistent with the prominent anatomical properties of the cerebello-cerebral projections that for the most part are crossed [6,10]. ...
... However, in the present study cerebral regions ipsilateral to the lesioned cerebellum, namely caudate nucleus and putamen, were also found to show significant GM alterations. Similar ipsilesional changes have also been observed in the cerebral cortex in a previous VBM study [12]. Bilateral cerebellar influences over cerebral cortex are also supported by lesional studies in rodents showing abnormal activity in the ipsilesional sensorimotor cortex [47] not to mention that ipsilateral connections between cerebellum and cerebral cortex have also been shown [48][49]. ...
Article
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Over the last decades, the importance of cerebellar processing for cortical functions has been acknowledged and consensus was reached on the strict functional and structural cor-tico-cerebellar interrelations. From an anatomical point of view strictly contralateral interconnections link the cerebellum to the cerebral cortex mainly through the middle and superior cerebellar peduncle. Diffusion MRI (dMRI) based tractography has already been applied to address cortico-cerebellar-cortical loops in healthy subjects and to detect diffusivity alteration patterns in patients with neurodegenerative pathologies of the cerebellum. In the present study we used dMRI-based tractography to determine the degree and pattern of pathological changes of cerebellar white matter microstructure in patients with focal cerebellar lesions. Diffusion imaging and high-resolution volumes were obtained in patients with left cerebellar lesions and in normal controls. Middle cerebellar peduncles and superior cerebellar peduncles were reconstructed by multi fiber diffusion tractography. From each tract, measures of microscopic damage were assessed, and despite the presence of unilateral lesions, bilateral diffusivity differences in white matter tracts were found comparing patients with normal controls. Consistently, bilateral alterations were also evidenced in specific brain regions linked to the cerebellum and involved in higher-level functions. This could be in line with the evidence that in the presence of unilateral cerebellar lesions, different cognitive functions can be affected and they are not strictly linked to the side of the cerebellar lesion. © 2017 Olivito et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
... Damage to the right cerebellar hemisphere has been related to language deficits [36] and general impairments in cognitive performance [5,41,42]. The latter not only could be associated with atrophic changes in left cerebral cortices conditioned by right-lateralized cerebellar insults [42], but also could reflect the impact of language disorders over neuropsychological test performance [6]. ...
... Damage to the right cerebellar hemisphere has been related to language deficits [36] and general impairments in cognitive performance [5,41,42]. The latter not only could be associated with atrophic changes in left cerebral cortices conditioned by right-lateralized cerebellar insults [42], but also could reflect the impact of language disorders over neuropsychological test performance [6]. ...
Article
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The cerebellar cognitive affective syndrome (CCAS) has been consistently described in patients with acute/subacute cerebellar injuries. However, studies with chronic patients have had controversial findings that have not been explored with new cerebellar-target tests, such as the CCAS scale (CCAS-S). The objective of this research is to prove and contrast the usefulness of the CCAS-S and the Montreal Cognitive Assessment (MoCA) test to evaluate cognitive/affective impairments in patients with chronic acquired cerebellar lesions, and to map the cerebellar areas whose lesions correlated with dysfunctions in these tests. CCAS-S and MoCA were administrated to 22 patients with isolated chronic cerebellar strokes and a matched comparison group. The neural bases underpinning both tests were explored with multivariate lesion-symptom mapping (LSM) methods. MoCA and CCAS-S had an adequate test performance with efficient discrimination between patients and healthy volunteers. However, only impairments determined by the CCAS-S resulted in significant regional localization within the cerebellum. Specifically, patients with chronic cerebellar lesions in right-lateralized posterolateral regions manifested cognitive impairments inherent to CCAS. These findings concurred with the anterior-sensorimotor/posterior-cognitive dichotomy in the human cerebellum and revealed clinically intra- and cross-lobular significant regions (portions of right lobule VI, VII, Crus I-II) for verbal tasks that overlap with the “language” functional boundaries in the cerebellum. Our findings prove the usefulness of MoCA and CCAS-S to reveal cognitive impairments in patients with chronic acquired cerebellar lesions. This study extends the understanding of long-term CCAS and introduces multivariate LSM methods to identify clinically intra- and cross-lobular significant regions underpinning chronic CCAS.
... Visual comparison between our studies suggest that the CbH in our cohort were relatively smaller, which could be an influential factor in the observed cortical morphology. In adult patients with cerebellar injury, using VBM, Clausi et al. (2007) showed diminished cortical gray matter volume occurred only after right cerebellar injury 46 . Conversely, another study in adult patients with cerebellar injury showed bilateral decreases in cortical gray matter volume 47 . ...
... The interpretation of the differences between case-cohort groups is not straightforward. For instance, homologous regions of the ipsilateral hemisphere might be included in a broader neuronal network that indirectly, for instance via the corpus callosum, suffers from the functional disconnection of the cerebellum 46 . This hypothesis lends support from studies that suggest that the injury is not confined to the site where it initially occurred and that it may result in experience-dependent structural remodeling of the entire cerebello-cerebral circuit 48,52,64 . ...
Article
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The cerebellum is connected to numerous regions of the contralateral side of the cerebrum. Motor and cognitive deficits following neonatal cerebellar hemorrhages (CbH) in extremely preterm neonates may be related to remote cortical alterations, following disrupted cerebello-cerebral connectivity as was previously shown within six CbH infants. In this retrospective case series study, we used MRI and advanced surface-based analyses to reconstruct gray matter (GM) changes in cortical thickness and cortical surface area in extremely preterm neonates (median age = 26; range: 24.9–26.7 gestational weeks) with large isolated unilateral CbH (N = 5 patients). Each CbH infant was matched with their own preterm infant cohort (range: 20–36 infants) based on sex and gestational age at birth. On a macro level, our data revealed that the contralateral cerebral hemisphere of CbH neonates did not show less cortical thickness or cortical surface area than their ipsilateral cerebral hemisphere at term. None of the cases differed from their matched cohort groups in average cortical thickness or average cortical surface area in the ipsilateral or contralateral cerebral hemisphere. On a micro (i.e. vertex) level, we established high variability in significant local cortical GM alteration patterns across case-cohort groups, in which the cases showed thicker or bigger volume in some regions, among which the caudal middle frontal gyrus, insula and parahippocampal gyrus, and thinner or less volume in other regions, among which the cuneus, precuneus and supratentorial gyrus. This study highlights that cerebellar injury during postnatal stages may have widespread bilateral influence on the early maturation of cerebral cortical regions, which implicate complex cerebello-cerebral interactions to be present at term birth.
... This evidence has been further supported by neuroimaging studies in patients with cerebellar damage using voxel-based lesion-symptom mapping that have shown a link between damage to the right Crus I and verbal fluency deficits (Richter, Gerwig, Aslan, et al., 2007), while damage to right lobules VII through IX was associated with poorer scores on the Boston Naming Test (Stoodley, MacMore, Makris, et al., 2016). As suggested by a whole-brain voxel-based morphometry study (Clausi, Bozzali, Leggio, et al., 2009) in patients affected by isolated cerebellar damage, gray matter (GM) changes may occur in supratentorial regions due to the reduced input via cerebello-cortical pathways and result in the observed functional impairment. Specifically, reduced GM volume in the left superior temporal gyrus has been shown after isolated right cerebellar damage and correlated with verbal fluency deficits in patients (Clausi et al., 2009). ...
... As suggested by a whole-brain voxel-based morphometry study (Clausi, Bozzali, Leggio, et al., 2009) in patients affected by isolated cerebellar damage, gray matter (GM) changes may occur in supratentorial regions due to the reduced input via cerebello-cortical pathways and result in the observed functional impairment. Specifically, reduced GM volume in the left superior temporal gyrus has been shown after isolated right cerebellar damage and correlated with verbal fluency deficits in patients (Clausi et al., 2009). It is worth noting that, although most studies have indicated crossed cerebro-cerebellar language lateralization (Méndez Orellana, Visch-Brink, Vernooij, et al., 2015;Starowicz-Filip, Chrobak, Moskała, et al., 2017), clinical and neuroimaging findings have also suggested that the left cerebellar hemisphere contributes to the mediation of language via ipsilateral cerebello-cortical pathways (Murdoch & Whelan, 2007). ...
Book
This edited volume provides the first presentation of the state-of-the-art in the application of modern Neuroscience research in predicting, preventing and alleviating the negative sequelae of neurodevelopmental, acquired, or neurodegenerative conditions on speech and language. It brings together contributions from several leading experts in a markedly broad range of disciplines, including Speech and Language Therapy, Neuropsychology and Neurology, but also Neurosurgery, Neuroimaging and Neurostimulation, as well as Engineering and Genetics.
... decreased perfusion or metabolism in cerebral areas following damage to the cerebellumhas been proposed as a mechanism explaining the transient mutism that occurs in 11-29% of patients after cerebellar tumour resections (Gudrunardottir et al., 2011). Further, reduced density of cerebral grey matter has been reported in patients after focal cerebellar lesions acquired in adulthood (Clausi et al., 2009). As would be expected based on known cerebello-cerebral anatomical connections, these reductions were primarily seen contralaterally to the cerebellar lesions. ...
... The current white matter findings are consistent with previous reports of reduced supratentorial FA in cerebellar tumour patients (Rueckriegel et al., 2010;Soelva et al., 2013), and widespread changes in extra-cerebellar white matter thus appears to be a robust and replicable finding in this patient group, even when treatment is limited to surgical intervention, avoiding the known risk associated with radiation therapy (Hoang et al., 2014;Uh et al., 2013) and the possible risk associated with chemotherapy (Simó et al., 2013). While we are not aware of other studies investigating supratentorial grey matter following cerebellar tumour surgery, our results stand in marked contrast to reports of decreased cerebral grey matter volume following cerebellar injury in infancy (Bolduc et al., 2011;Limperopoulos et al., 2010; and decreased grey matter density following lesions acquired in adulthood (Clausi et al., 2009). Taken together, these findings suggest that long term effect on cerebral structures may depend on the developmental stage at cerebellar injury, in line with the notion of sensitive periods for brain development (Wang et al., 2014). ...
Article
The cerebellum is connected to extensive regions of the cerebrum, and cognitive deficits following cerebellar lesions may thus be related to disrupted cerebello-cerebral connectivity. Moreover, early cerebellar lesions could affect distal brain development, effectively inducing long-term changes in brain structure and cognitive function. Here, we characterize supratentorial brain structure and cognitive function in 20 adult patients treated for cerebellar tumours in childhood (mean age at surgery: 7.1 years) and 26 matched controls. Relative to controls, patients showed reduced cognitive function and increased grey matter density in bilateral cingulum, left orbitofrontal cortex and the left hippocampus. Within the patient group, increased grey matter density in these regions was associated with decreased performance on tests of processing speed and executive function. Further, diffusion tensor imaging revealed widespread alterations in white matter microstructure in patients. While current ventricle volume (an index of previous hydrocephalus severity it patients) was associated with grey matter density and white matter microstructure in patients, this could only partially account for the observed group differences in brain structure and cognitive function. In conclusion, our results show distal effects of cerebellar lesions on cerebral integrity and wiring, likely caused by a combination of neurodegenerative processes and perturbed neurodevelopment.
... mental rotation associated with lesions in left VII, Boston Naming Task localized to right VII), which are consistent with earlier studies (Levisohn et al. 2000;Scott et al. 2001), the majority of the cerebellar regions associated with poorer cognitive performance were right-lateralized. This is consistent with the finding that right cerebellar damage leads to reduced grey matter in contralateral frontal, parietal and temporal cortices and is associated with lower scores on neuropsychological measures (Clausi et al., 2009). Clausi et al. reported that left cerebellar damage was not associated with neuropsychological or cerebral grey matter abnormalities, ...
... Lesion-symptom mapping in cerebellar stroke 47 although only two of seven patients with left cerebellar damage in that study had lesions involving the dentate nucleus, whereas the majority (6/8) of the right cerebellar patients had dentate damage (Clausi et al., 2009). This is consistent with the finding that involvement of the cerebellar deep nuclei is a predictor of cognitive deficits in cerebellar lesions (Tedesco et al., 2011). ...
Article
Full-text available
Cerebellar lesions can cause motor deficits and/or the cerebellar cognitive affective syndrome (CCAS; Schmahmann's syndrome). We used voxel-based lesion-symptom mapping to test the hypothesis that the cerebellar motor syndrome results from anterior lobe damage whereas lesions in the posterolateral cerebellum produce the CCAS. Eighteen patients with isolated cerebellar stroke (13 males, 5 females; 20–66years old) were evaluated using measures of ataxia and neurocognitive ability. Patients showed a wide range of motor and cognitive performance, from normal to severely impaired; individual deficits varied according to lesion location within the cerebellum. Patients with damage to cerebellar lobules III-VI had worse ataxia scores; as predicted, the cerebellar motor syndrome resulted from lesions involving the anterior cerebellum. Poorer performance on fine motor tasks was associated primarily with strokes affecting the anterior lobe extending into lobule VI, with right-handed finger tapping and peg-placement associated with damage to the right cerebellum, and left-handed finger tapping associated with left cerebellar damage. Patients with the CCAS in the absence of cerebellar motor syndrome had damage to posterior lobe regions, with lesions leading to significantly poorer scores on language (e.g. right Crus I and II extending through IX), spatial (bilateral Crus I, Crus II, and right lobule VIII), and executive function measures (lobules VII-VIII). These data reveal clinically significant functional regions underpinning movement and cognition in the cerebellum, with a broad anterior-posterior distinction. Motor and cognitive outcomes following cerebellar damage appear to reflect the disruption of different cerebro-cerebellar motor and cognitive loops.
... For this reason, analyzing patients with this condition via whole-brain voxelbased morphometry (VBM) -this is a technique designed to investigate all aimed voxels independentlyappears to be a very suitable approach for conducting exploratory research aimed at uncovering the unknown functional/structural relationships between the cerebellum and cerebrum. VBM has already been used in several cerebellar studies concerned with focal cerebellar damage (Clausi et al., 2009) as well as ataxia and cerebellar degeneration. Ataxia is the lack of coordination of voluntary movements and its most common cause is a cerebellar dysfunction of genetic origin. ...
Article
In recent years the cerebellum has been attributed amore 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.
... events for determining long-term functional prognosis (Binkofski et al., 1996;Freret et al., 2006;Immonen et al., 2009). Studies that have combined functional MRI and tests that assess specific brain functions have shown clearly that remote degeneration contributes to late-stage sensorimotor disturbances and cognitive impairment (Demeurisse et al., 1991;Ziemus et al., 2007;Clausi et al., 2009). ...
Article
Functional impairment after development of focal CNS lesions depends highly on damage that occurs in regions that are remote but functionally connected to the primary lesion site. These remote effects include cell death and structural changes, and they are important predictors of outcome in several pathologies, such as stroke, multiple sclerosis, and brain trauma. A greater understanding of the neuropathological mechanisms that exist in regions that are remote from focal primary lesions is therefore essential for the development of neuroprotective strategies. Endocannabinoids constitute a novel class of lipids that regulate mammalian cell apoptosis and the pathogenesis of neuroinflammatory and neurodegenerative diseases. In addition to well-described pharmacological actions in the brain, such as analgesia, hypokinesia, and hypothermia, endocannabinoids have been recently reported to control neuronal cell fate in various neuropathological conditions. Following brain injury, endocannabinoids are released, causing both protective and degenerative effects. Several hypotheses have been proposed to explain their role, but the mechanisms by which they act are largely unknown. New evidence indicates that the endocannabinoid system is a key participant in the determination of cell fate in remote cell death and its associated mechanisms. This review addresses recent findings on endocannabinoid function, focusing particularly on the relationships between the nitrergic, purinergic, and endocannabinoid systems.
... With the advent of sensitive techniques such as magnetic resonance imaging (MRI), cerebellar ataxias (CAs) are being growingly recognized [11,36,57,145,165,224]. There is a medical need to develop effective therapies in this group of disabling disorders for which no cure is currently available. ...
Article
Full-text available
Cerebellar ataxias are a group of disabling neurological disorders. Patients exhibit a cerebellar syndrome and can also present with extra-cerebellar deficits, namely pigmentary retinopathy, extrapyramidal movement disorders, pyramidal signs, cortical symptoms (seizures, cognitive impairment/behavioural symptoms), and peripheral neuropathy. Recently, deficits in cognitive operations have been unraveled. Cerebellar ataxias are heterogeneous both at the phenotypic and genotypic point of view. Therapeutical trials performed during these last 4 decades have failed in most cases, in particular because drugs were not targeting a deleterious pathway, but were given to counteract putative defects in neurotransmission. The identification of the causative mutations of many hereditary ataxias, the development of relevant animal models and the recent identifications of the molecular mechanisms underlying ataxias are impacting on the development of new drugs. We provide an overview of the pharmacological treatments currently used in the clinical practice and we discuss the drugs under development.
... Higher-order cerebral regions, such as the DLPFC, the parietal and the superior temporal cortices project to the cerebellum through the pontine nuclei [2][3][4]. Moreover, a recent VBM study [37] demonstrated that focal cerebellar lesions lead to both specific cognitive deficits (in attention, language and spatial memory domains) and atrophies in the frontal and temporal cortices, without loss of GM volume in the cerebellum. All these evidences strengthen the idea that the detected GM tissue loss in associative cortical areas, as well as the specific cognitive decline, may arise from Wallerian degeneration and diaschisis induced by cerebellar WM lesions characterizing the RR-MS patients with cerebellar symptoms. ...
Article
Full-text available
Multiple sclerosis (MS) is a demyelinating disease affecting the central nervous system, frequently associated with cognitive impairments. Damages of the cerebellum are very common features of patients with MS, although the impact of this clinical factor is generally neglected. Recent evidence from our group demonstrated that MS patients with cerebellar damages are characterized by selective cognitive dysfunctions related to attention and language abilities. Here, we aimed at investigating the presence of neuroanatomical abnormalities in relapsing-remitting MS patients with (RR-MSc) and without (RR-MSnc) cerebellar signs. Twelve RR-MSc patients, 14 demographically, clinically, and radiologically, matched RR-MSnc patients and 20 controls were investigated. All patients underwent neuropsychological assessment. After refilling of FLAIR lesions on the 3D T1-weighted images, VBM was performed using SPM8 and DARTEL. A correlation analysis was performed between VBM results and neuropsychological variables characterizing RR-MSc patients. Despite a similar clinical status, RR-MSc patients were characterized by more severe cognitive damages in attention and language domains with respect to RR-MSnc and controls. With respect to controls, RR-MSnc patients were characterized by a specific atrophy of the bilateral thalami that became more widespread (including motor cortex) in the RR-MSc group (FWE < 0.05). However, consistent with their well-defined neuropsychological deficits, RR-MSc group showed atrophies in the prefrontal and temporal cortical areas when directly compared with RR-MSnc group. Our results demonstrated that RR-MS patients having cerebellar signs were characterized by a distinct neuroanatomical profile, mainly involving cortical regions underpinning executive functions and verbal fluency.
... In addition, consistently with some [46,47] but not other studies [24,44,45], our entire cohort of AD patients showed a well localized cluster of GM atrophy in the posterior cerebellum (crus I, crus II, lobules VI and VIII). This is not surprising as it is widely accepted that the cerebellum plays a role not only in motor functions, but also in cognitive and emotion processing [48][49][50]. Interestingly, the posterior part of the cerebellum has been shown to take part in the regulation of memory, executive functions, visuo-spatial abilities, language, and attention [50]. ...
Article
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Constructional apraxia (CA) is often, but not always, observed in patients with Alzheimer's disease (AD). CA is usually explained by impairment of either basic perceptual and motor abilities, or of executive functions. This study aims to evaluate the structural correlates of CA in AD. Forty-eight patients with AD and 20 healthy age-matched controls underwent a thorough neuropsychological investigation and an MRI scan to collect high-resolution T1-weighted data. Patients were classified as having (ADca) or not having (ADnonca) CA based on performance on the Freehand copying of drawings task. T1-weighted volumes were processed according the voxel-based morphometry protocol, to assess the presence of significant differences in local grey matter volume in patients compared to controls and in ADca compared to ADnonca. Post-hoc, the mean grey matter volume of clusters that resulted significantly different between groups was regressed against the neuropsychological scores in which the two patient groups performed differently. A pre-senile disease onset was significantly more frequent in patients with CA compared to ADnonca. ADca patients also showed worse performances than patients with ADnonca at some tests requiring the processing of visuo-spatial data and testing working memory. They also showed widespread reductions in grey matter volume, mainly located in areas known to be implicated in object recognition and localization, and in maintenance and re-orienting of spatial attention. These findings suggest that the occurrence of CA in AD is often associated with a peculiar clinical onset (i.e., pre-senile), neuropsychological profile, and distribution of grey matter atrophy.
... Notably, the effects of DCN damage that we observed are consistent with previous studies on various cognitive domains [28,78,79]. However, our findings must be confirmed in future studies using advanced methods to better characterize the site of the lesion in the DCN [80]. ...
Article
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Executive control of motor responses is a psychological construct of the executive system. Several studies have demonstrated the involvement of the cerebral cortex, basal ganglia, and thalamus in the inhibition of actions and monitoring of performance. The involvement of the cerebellum in cognitive function and its functional interaction with basal ganglia have recently been reported. Based on these findings, we examined the hypothesis of cerebellar involvement in executive control by administering a countermanding task in patients with focal cerebellar damage. The countermanding task requires one to make a movement in response to a 'go' signal and to halt it when a 'stop' signal is presented. The duration of the go process (reaction time; RT), the duration of the stop process (stop signal reaction time; SSRT), and their relationship, expressed by a psychometric function, are recorded as measures of executive control. All patients had longer go process duration in general and in particular, as a proactive control, as demonstrated by the increase in RT after erroneously performed stop trials. Further, they were defective in the slope of the psychometric function indicating a difficulty on triggering the stop process, although the SSRT did not differ from controls. Notably, their performance was worse when lesions affected deep cerebellar nuclei. Our results support the hypothesis that the cerebellum regulates the executive control of voluntary actions. We speculate that its activity is attributed to specific cerebellar influence over the cortico-striatal loop.
... Moreover, two volumetric studies described significant correlations between the impairment of executive functions and loss of grey matter volumes in the cerebellum [40] and in the dorsolateral prefrontal cortex as well as between language performance and atrophy of the superior temporal cortex [42]. The hypothesis that an altered communication of the cerebellum with higher-order cortical areas contributes to the dysfunctional cognitive profile of MS patients is indirectly supported by a recent volumetric study investigating patients with non-demyelinating focal cerebellar lesions [43]. The authors described specific deficits in executive functions and language performance in association with grey matter reductions of the frontal and temporal cortices. ...
Article
Full-text available
In multiple sclerosis (MS), cerebellar signs and symptoms as well as cognitive dysfunction are frequent and contribute to clinical disability with only poor response to symptomatic treatment. The current consensus paper highlights the broad range of clinical signs and symptoms of MS patients, which relate to cerebellar dysfunction. There is considerable evidence of cerebellar involvement in MS based on clinical, histopathological as well as structural and functional magnetic resonance imaging (MRI) studies. The review of the recent literature, however, also demonstrates a high variability of results. These discrepancies are, at least partially, caused by the use of different techniques and substantial heterogeneity among the patient cohorts in terms of disease duration, number of patients, and progressive vs. relapsing disease courses. Moreover, the majority of studies were crosssectional, providing little insight into the dynamics of cerebellar involvement in MS. Some links between the histopathological changes, the structural and functional abnormalities as captured by MRI, cerebellar dysfunction, and the clinical consequences are starting to emerge and warrant further study. A consensus is formed that this line of research will benefit from advances in neuroimaging techniques that allow to trace cerebellar involvement at higher resolution. Using a prospective study design, multimodal high-resolution cerebellar imaging is highly promising, particularly in patients who present with radiologically or clinically isolated syndromes or newly diagnosed MS.
... Either using a clinical model of cerebellar damage (MS patients with cerebellar signs) or generally investigating MS patients, it is evident that performance mainly related to executive functions is strictly related to the functionality and the integrity of the cerebellum. This neuropsychological pattern has also been confirmed by previous lesion studies demonstrating that focal cerebellar lesions per se lead to specific cognitive deficits in executive functions and language domains [12,33]. ...
Research
Full-text available
In recent years, a high number of studies have demonstrated that neuropsychological functions are altered in multiple sclerosis (MS) patients with cerebellar lesions, mainly including attention, working memory and verbal fluency. Since the present literature is often elusive on this topic, we aim to provide a comprehensive report about the real impact of cerebellar damages (evaluated as volume, lesions or connectivity measures) on cognitive functions. In particular in this review, we report and discuss recent works from 2009 to 2015, which have demonstrated the key role of the cerebellum in cognitive impairment of MS patients.
... Cortical regions that govern this organization include the premotor, prefrontal, and parietal areas-all of which are concerned with motor and nonmotor function [11,[15][16][17]. The anatomical organization of the cerebello-cortical loop was first studied in animal models, and while the topography of the corticoponto-cerebellar [18] and cerebello-thalamo-cortical systems [14,19] has been detailed in monkeys, only recently the advances in neuroimaging techniques have allowed researchers to confirm this organization in humans [20][21][22][23][24]. ...
Article
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Although cerebellar-cortical interactions have been studied extensively in animal models and humans using modern neuroimaging techniques, the effects of cerebellar stroke and focal lesions on cerebral cortical processing remain unknown. In the present study, we analyzed the large-scale functional connectivity at the cortical level by combining high-density electroencephalography (EEG) and source imaging techniques to evaluate and quantify the compensatory reorganization of brain networks after cerebellar damage. The experimental protocol comprised a repetitive finger extension task by 10 patients with unilateral focal cerebellar lesions and 10 matched healthy controls. A graph theoretical approach was used to investigate the functional reorganization of cortical networks. Our patients, compared with controls, exhibited significant differences at global and local topological level of their brain networks. An abnormal rise in small-world network efficiency was observed in the gamma band (30–40 Hz) during execution of the task, paralleled by increased long-range connectivity between cortical hemispheres. Our findings show that a pervasive reorganization of the brain network is associated with cerebellar focal damage and support the idea that the cerebellum boosts or refines cortical functions. Clinically, these results suggest that cortical changes after cerebellar damage are achieved through an increase in the interactions between remote cortical areas and that rehabilitation should aim to reshape functional activation patterns. Future studies should determine whether these hypotheses are limited to motor tasks or if they also apply to cerebro-cerebellar dysfunction in general.
... For this reason, analyzing patients with this condition via whole-brain voxelbased morphometry (VBM) -this is a technique designed to investigate all aimed voxels independentlyappears to be a very suitable approach for conducting exploratory research aimed at uncovering the unknown functional/structural relationships between the cerebellum and cerebrum. VBM has already been used in several cerebellar studies concerned with focal cerebellar damage (Clausi et al., 2009) as well as ataxia and cerebellar degeneration. Ataxia is the lack of coordination of voluntary movements and its most common cause is a cerebellar dysfunction of genetic origin. ...
Article
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.
... The evidence of motor, cognitive, and emotional impairments in presence of cerebellar damage has been linked to alterations of cerebro-cerebellar networks (Broich et al., 1987;Clausi et al., 2009;Komaba et al., 2000;Baillieux et al., 2010). ...
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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.
... The evidence of motor, cognitive, and emotional impairments in presence of cerebellar damage has been linked to alterations of cerebrocerebellar networks (Broich et al., 1987;Clausi et al., 2009;Komaba et al., 2000;Baillieux et al., 2010). distinct functional networks (Allen et al., 2005;Habas et al., 2009;De Vico Fallani et al., 2016) clearly related to different functional processes. ...
Poster
Neural substrates of motor and cognitive dysfunctions in SCA2 patients: a network-based statistical analysis
... Our study is not without limitations. First, infratentorial lesions have not been considered, although both grey and white matter lesions in the cerebellum could have an impact on cortico-cerebellar disconnection [56]. However, lesions impact DTI metrics, and their effect is therefore included within the variables. ...
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Background The posterior cerebellar lobules seem to be the anatomical substrate of cognitive cerebellar processes, but their microstructural alterations in multiple sclerosis (MS) remain unclear. Objectives To correlate diffusion metrics in lobules VI to VIIIb in persons with clinically isolated syndrome (PwCIS) and in cognitively impaired persons with MS (CIPwMS) with their cognitive performances. Methods Sixty-nine patients (37 PwCIS, 32 CIPwMS) and 36 matched healthy subjects (HS) underwent 3T magnetic resonance imaging, including 3D T1-weighted and diffusion tensor imaging (DTI). Fractional anisotropy (FA) and mean diffusivity (MD) were calculated within each lobule and in the cerebellar peduncles. We investigated the correlations between cognitive outcomes and the diffusion parameters of cerebellar sub-structures and performed multiple linear regression analysis to predict cognitive disability. Results FA was generally lower and MD was higher in the cerebellum and specifically in the vermis Crus II, lobules VIIb and VIIIb in CIPwMS compared with PwCIS and HS. In hierarchical regression analyses, 31% of the working memory z score variance was explained by FA in the left lobule VI and in the left superior peduncle. Working memory was also associated with MD in the vermis Crus II. FA in the left lobule VI and right VIIIa predicted part of the information processing speed (IPS) z scores. Conclusion DTI indicators of cerebellar microstructural damage were associated with cognitive deficits in MS. Our results suggested that cerebellar lobular alterations have an impact on attention, working memory and IPS.
... A similar spread of pathology has been demonstrated in stroke, where acute infarcts were found to produce cortical thinning in connected areas via disruption to connecting white-matter fibres (Duering et al., 2015). Furthermore, adults who sustain unilateral cerebellar damage, particularly involving the DN, have shown reduced cortical grey-matter volume, primarily in the contralateral hemisphere, relative to controls (Clausi et al., 2009). This evidence suggests that it is possible for cerebellar lesions to have a downstream impact on cerebral white-matter and the cerebral cortex. ...
... Effects of cerebellar damage on red nucleus anatomy and functions have been addressed by Tsukahara (Tsukahara et al. 1983) and were among the first demonstration of postlesional brain plasticity mechanisms in the brain. Thalamic and cortical changes have been addressed by many authors in humans (Jissendi et al. 2008;Clausi et al. 2009), but seldom analyzed in animal models. The well-described anatomical efferent-afferent organization of the cerebellar system and the density of the major afferent sources in two well-defined brainstem structures-the inferior olive and pontine nuclei-constitute an optimal model that can be used to examine the mechanism of trans-synaptic degeneration-retrograde or anterograde-occurring in brain regions that are far, but functionally connected to the lesion site. ...
Chapter
Hemicerebellectomy (HCB) is characterized by ablation of half of the vermis with one cerebellar hemisphere, including the deep cerebellar nuclei, while sparing the vestibular nuclei and all surrounding structures. This approach has been adopted widely by many groups mainly in rats in various contexts of research. The purpose of this chapter is to review old and recent data focusing on morphological as well as functional data obtained in this model in addressing cerebellar function and brain plasticity mechanisms.
... Over the years, increasing evidence of the cerebellar involvement in cognition has been reached leading to the description of a clinical condition, referred to as the "Schmahmann's syndrome" (SS) [2]. Such a condition occurs in the presence of lesions of the cognitive and limbic part of the cerebellum (i.e., posterior lobes; lobules VI, Crus I and II; lobule IX) and is characterized by a complex variety of cognitive deficits [3,4]. Impaired cognitive performance, involving language, executive, visuospatial and sequencing functions has also been found in patients with cerebellar atrophy [4,5], a condition characterized by diffuse degeneration of the cerebellar cortex, which is regarded as the central computational integrator of the cerebellar system [6]. ...
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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.
... Nevertheless, previous studies have also reported bilateral structural alterations in cerebral grey matter density and in white matter tracts as a result of unilateral cerebellar lesions (Clausi et al., 2009;Olivito et al., 2017). This may explain why cognitive dysfunctions, possibly linked to a primary damage in a specific side of the cerebellum, can also be associated to structural changes in ipsilateral cerebral regions that seem to be opposed to the cortical lateralization of the cognitive process evaluated. ...
Article
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Spinocerebellar Ataxia Type 7 (SCA7) is a neurodegenerative disorder caused by cytosine‐adenine‐guanine (CAG) repeat expansion. It is clinically characterized by ataxia and visual loss. To date, little is known about SCA7 cognitive impairments and its relationship with grey matter volume (GMV) changes. The aim of this study was to explore SCA7 patients’ performance in specific components of auditory‐verbal neuropsychological tests and to correlate their scores with genetic mutation, severity of ataxia and GMV. We assessed verbal memory and verbal fluency proficiencies in 31 genetically confirmed SCA7 patients, and compared their results with 32 healthy matched volunteers; we also correlated CAG repeats and severity of motor symptoms with performance in the auditory‐verbal tests. SCA7 patients exhibited deficiencies in several components of these cognitive tasks, which were independent of motor impairments and showed no relation to CAG repeats. Based on Resonance Images performed in 27 patients we found association between ataxia severity and GMV in “sensoriomotor” cerebellum, as well as correlations of impaired verbal memory and semantic fluency scores with GMV in association cortices, including the right parahippocampal gyrus. To our knowledge, this is the first report of deficits in the organization of semantic information and in the evocation of verbal material, as well as greater susceptibility to proactive interference in SCA7 patients. These findings bring novel information about specific cognitive abilities in SCA7 patients, particularly verbal memory and fluency, and their relation with GMV variations in circumscribed brain regions, including association cortices known to have functional relationships with the cerebellum.
... Furthermore, a decline of verbal fluency has been observed only in MS patients with cerebellar damages, that result in being correlated with gray matter loss in the superior temporal cortex [45]. Additionally, cerebellar damages and atrophies in the frontal and temporal cortices induce poor verbal fluency and attention [46]. ...
Article
Multiple sclerosis (MS) is characterized by central nervous system lesions that lead to neurological dysfunctions including fatigue, depression and anxiety. MS is affecting almost 2.3 million people around the world, with the significant highest prevalence in the North America. MS also affects different cognitive abilities, such as attention, memory and executive functions. Furthermore, a significant impairment in verbal fluency and naming abilities in patients with MS has been reported. RehaCom, is a software that has improvement effects on cognitive functions. The goal of this research is to investigate the effect of treatment with RehaCom on verbal performance in patients with MS. To select the participants, 60 patients with MS who referred to our clinic were chosen randomly and divided into Control (n = 30) and Experimental (n = 30) groups. The participants in the experimental group were treated by RehaCom software for 10 sessions during 5 weeks (2 sessions per week and each session was 1 h). Controlled Oral Word Association Test (COWAT) and California Verbal Learning Test - Second Edition (CVLT-II), were used to assess verbal performance (verbal fluency, and verbal learning and memory) at weeks 0 (baseline), 5 (post-test) and 10 (follow-up). The results showed that, treatment with RehaCom improved verbal performance in patient with MS, at both post-test and follow-up stages. In conclusion, treatment with RehaCom cognitive rehabilitation software can improve verbal fluency, and verbal learning and memory in patient with MS, possibly by affecting the brain regions involved in language performance.
... Lastly, because we did not have T1-weighted MRI images from the majority of patients, we were not able to reliably perform a wholebrain voxel-based morphometry (VBM) analysis to exclude the presence of gray matter degeneration in cortical areas involved in emotion recognition and decision-making, such as the pre-frontal cortex. A reduction of gray matter volume in cerebellar projection areas could have been related to the focal cerebellar damage [39]. ...
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An increasing amount of research has shown a cerebellar involvement in higher order cognitive functions, including emotional processing and decision-making. However, it has not been investigated whether impairments in facial emotion recognition, which could be a marker of impaired emotional experiences, are related to risky decision-making in these patients. Therefore, we aimed to investigate facial emotion recognition and risky decision-making in these patients as well as to investigate a relationship between these constructs. Thirteen patients with a discrete, isolated, cerebellar lesion as a consequence of a stroke were included in the study. Emotion recognition was assessed with the Facial Expressions of Emotions—Stimuli and Test (FEEST). Risk-taking behavior was assessed with the Action Selection Test (AST). Furthermore, 106 matched healthy controls performed the FEEST and 20 matched healthy controls performed the AST. Compared with healthy controls, patients were significantly worse in the recognition of emotional expressions and they took significantly more risks. In addition, a worse ability to recognize fearful facial expressions was strongly related to an increase in risky decisions in the AST. Therefore, we suggest that tests of emotion recognition should be incorporated into the neuropsychological assessment after cerebellar stroke to boost detection and treatment of these impairments in these patients.
... The last three papers apply high-resolution structural magnetic resonance imaging (MRI) combined with newer analysis methods to cerebellar pathologies to map cerebellar motor symptoms (Timmann et al., 2009) and to address cerebro-cerebellar interactions in subjects with focal cerebellar lesions (Clausi et al., 2009). Schmahmann et al. (2009) analyze imaging/behavioral data from patients with cerebellar strokes, concluding that there are major differences in the localization and severity of motor (anterior lobe) and cognitive (posterior lobe) deficits. ...
Chapter
Since the end of nineteenth century, the simplicity of neuronal architecture of the cerebellar system has attracted neuroscientist and thus cerebellum has become one of the favorite targets for testing the cellular or systemic functional hypothesis of neural function. Thus the classical lesion approach, which consists in damaging a structure to test the function, has been applied many times.
Chapter
A traditional approach to studying cerebellar function is examining impairment in human subjects with cerebellar disease. High-resolution structural brain imaging coupled with tools that perform lesion-symptom mapping produced major advances in localization of function within the human cerebellum. Lesionsymptom mapping is also called lesion-behavior mapping and lesion-defi cit mapping. To localize function, patients should be included who have lesions restricted to the cerebellum. These patients are rare. Group sizes are commonly much smaller than in comparable studies with cerebral stroke. Methods will be discussed which are currently available to perform lesion-symptom mapping in patients with focal and degenerative cerebellar disease.
Objective In this prospective study, we aimed to investigate the presence and evolution of cerebellar cognitive affective syndrome in a cohort of isolated cerebellar stroke with no known cognitive or psychiatric impairment. We tried to distinguish the unconfounded effect of cerebellar lesions on neuropsychological processing. Methods After a meticulous exclusion procedure based on possible confounders, we recruited 14 patients and 13 age-matched healthy controls to the study, prospectively. All of the patients had a detailed initial neuropsychological assessment at the first week and a follow-up assessment at the 4th month after stroke. Results The prevalence of cognitive or behavioral-affective abnormalities in our cohort were 86% and 64% respectively. The patients exhibited mild and transient affective-behavioral abnormalities except for depressive symptoms that persisted in the subacute stage. They scored lower in general cognitive performance as revealed by mini mental test (p=0.001). Memory, executive functions, attention and working memory, central processing speed, and linguistic abilities were impaired (p<0.001; p=0.001; p=0.007; p=0.05; p<0.001 respectively). Improvement was evident only in memory domain of the cognitive functions in the subacute stage. Cognitive impairment was more likely with a medial or posterolateral infarct (p=0.014). Behavioral-affective abnormalities were not associated with a specific location in our cohort. Age seemed to negatively correlate with the recovery in general cognitive performance on the follow-up. Conclusions These findings show that acute denervation of cerebellocortical projections leads to mild affective-behavioral abnormalities, and full-blown cerebellar cognitive affective syndrome is rare. However, cognition was significantly affected after an acute cerebellar infarct even in a previously healthy, non-demented pure population.
Article
We aimed to compare concentrations of N-acetyl aspartate, myo-inositol, and other neurometabolites in the cerebellar vermis of offspring at risk for bipolar disorder (BD) and healthy controls to examine whether changes in these neuronal metabolite concentrations occur in at-risk offspring prior to the onset of mania. A total of 22 children and adolescents aged 9-17 years with a familial risk for bipolar I or II disorder [at-risk offspring with non-bipolar I disorder mood symptoms (AR)], and 25 healthy controls (HC) were examined using proton magnetic resonance spectroscopy at 3T to study metabolite concentrations in an 8-cc voxel in the cerebellar vermis. Decreased myo-inositol and choline concentrations in the vermis were seen in the AR group compared to HC (p<0.01). Decreased cellular metabolism and interference with second messenger pathways may be present in the cerebellar vermis in youth at risk for BD as evident by decreased myo-inositol and choline concentrations in this region. These results may be limited by a cross-sectional design, co-occurring diagnoses, and medication exposure. Longitudinal studies are necessary to determine whether early neurochemical changes can predict the development of mania. Improved methods for identifying children with certain neurochemical vulnerabilities may inform preventive and early intervention strategies prior to the onset of mania.
Chapter
Approaches to thinking about the cerebellum have historically been overshadowed by the view that it is a structure mainly involved in the regulation and coordination of motor control. During the past decades, neuroanatomical, neuroimaging, and clinical studies have substantially modified this traditional view and provided new insights and a body of evidence for cerebellar involvement in a wide range of nonmotor processes, such as cognitive, affective, and social processes. Within the broad range of functions in which the cerebellum is involved, several clinical studies have shown the occurrence of different types of speech and language impairments subsequent to cerebellar damage. In the first part of the present chapter, we briefly summarize the motor and nonmotor language impairments that have been reported after cerebellar damage in adults and the associated cerebello-cerebral network alterations. Starting from these clinical and neuroimaging data about the “linguistic cerebellum,” in the second part of the chapter, we provide an overview of the studies that used noninvasive transcranial neuromodulation techniques to further investigate the cerebellar role in speech and language domains. Furthermore, we show the current state of the art and translational potential of the use of cerebellar neuromodulation to improve speech and language functions after cortical and subcortical damage.
Article
Essential tremor (ET) is an involuntary postural oscillation. It is unclear to which extent motor cortical activity in preparation of volitional movement is abnormal in ET. We measured the Bereitschaftspotential (BP) to address this question. Given the known influence of the cerebello-dentato-thalamo-cortical projection in the generation of the BP, patients were divided into two groups, defined by purely postural tremor (ET(PT)) or additional presence of intention tremor (ET(IT)) and compared to healthy controls. BP was recorded during self-paced rapid wrist extension movements. The late BP (500-0 ms before movement onset) was increased over the mid-frontal area in ET(PT), whereas it was reduced over the mid-parietal area in ET(IT) when compared to healthy controls. In addition, the late BP was reduced over a widespread centro-parietal area in ET(IT) compared to ET(PT). Findings suggest that presence vs. absence of cerebellar signs (intention tremor) in ET results in differential affection of volitional preparatory motor cortical activity. The BP increase in ET(PT) may indicate compensatory activity, whereas the widespread centro-parietal BP reduction in ET(IT) suggests dysfunction of the cerebello-dentato-thalamo-cortical projection. Reduction of the late BP amplitude may serve as a surrogate marker for dysfunction of the cerebello-dentato-thalamo-cortical projection in ET.
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The cerebellum is known to project via the thalamus to multiple motor areas of the cerebral cortex. In this study, we examined the extent and anatomical organization of cerebellar input to multiple regions of prefrontal cortex. We first used conventional retrograde tracers to map the origin of thalamic projections to five prefrontal regions: medial area 9 (9m), lateral area 9 (9l), dorsal area 46 (46d), ventral area 46, and lateral area 12. Only areas 46d, 9m, and 9l received substantial input from thalamic regions included within the zone of termination of cerebellar efferents. This suggested that these cortical areas were the target of cerebellar output. We tested this possibility using retrograde transneuronal transport of the McIntyre-B strain of herpes simplex virus type 1 from areas of prefrontal cortex. Neurons labeled by retrograde transneuronal transport of virus were found in the dentate nucleus only after injections into areas 46d, 9m, and 9l. The precise location of labeled neurons in the dentate varied with the prefrontal area injected. In addition, the dentate neurons labeled after virus injections into prefrontal areas were located in regions spatially separate from those labeled after virus injections into motor areas of the cerebral cortex. Our observations indicate that the cerebellum influences several areas of prefrontal cortex via the thalamus. Furthermore, separate output channels exist in the dentate to influence motor and cognitive operations. These results provide an anatomical substrate for the cerebellum to be involved in cognitive functions such as planning, working memory, and rule-based learning.
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This study aimed at investigating the clinical usefulness of the Mental Deterioration Battery (MDB) in the neuropsychological diagnosis and characterization of the dementia syndrome. In this paper, we report: (a) normative data for various test scores derived from the analysis of performance of 340 normal subjects living in urban areas; (b) an evaluation of the reliability of the single tests and of the battery as a whole in differentiating normal subjects from patients affected by cognitive deterioration derived from the analysis of performance of 130 normal subjects living in rural areas and 134 patients affected by probable Alzheimer’s dementia; (c) a cluster analysis of performances of the 340 normal subjects in the standardization group to evaluate possible criteria of homogeneity according to which the various MDB scores tend to aggregate; (d) an analysis of performance profiles of 183 patients with right monohemispheric focal lesions, 159 patients with left unilateral lesions with aphasia and 131 left-lesioned nonaphasic patients to evaluate the specificity of the single tests of the battery in documenting a selective impairment of one of the two cerebral hemispheres. Results confirm the reliability of the MBD in discriminating between normal and demented patients and provide indications for use of the battery in differentiating qualitative patterns of cognitive impairment.
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The aims of this study were to investigate the pattern of cortical atrophy and the relationships between memory performances and the brain regions in Alzheimer's Disease (AD). optimized voxel-based morphometry (VBM) was applied to the MRI brain images of 18 probable AD and 18 healthy subjects (HS). Patients performed verbal and visuo-spatial episodic and shortterm memory tests. Contrasting of AD group with HS, and anatomobehavioural correlations were carried out in order to identify regional atrophic changes and neuro-cognitive aspects in AD group. We found evidence of gray matter (GM) volume reduction in AD in the medial temporal, parietal and frontal areas bilaterally and in the left anterior thalamic nuclei. Performance on the episodic memory delayed recall tests co-varied with GM volume in the left entorhinal cortex. The pattern of cortical atrophy likely reflects the heterogeneous level of dementia severity in our AD group. The anatomical region affected in the left hemisphere indicates a sufferance at multiple levels of the Polysynaptic Hippocampal Pathway, which is involved in declarative memory. Findings on the entorhinal cortex and the delayed memory scores support the role of the entorhinal cortex in episodic memory. Damage to the entorhinal cortex, deafferenting the hippocampus from neocortical inputs, interferes with episodic memory consolidation in AD patients.
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Eleven patients with relatively selective cerebellar degeneration and 11 normal control subjects underwent a comprehensive neurologic and neuropsychological examination. The neuropsychological tests assessed general intellectual ability, different aspects of memory (effortful, automatic, and implicit memory processes), speed of information processing, and verbal fluency (using both category and letter fluency tasks). The results indicated that cerebellar patients were significantly impaired only on tasks requiring the use of executive functions, such as the initiation/perseveration subtest of the Mattis Dementia Rating Scale or the fluency tests, and on memory measures requiring greater processing effort. They performed normally on automatic and implicit measures of memory. Performance on the effortful memory and executive measures was not associated with neurologic variables or mood state. After controlling for the initiation/perseveration deficit, the effortful memory scores of the cerebellar patients were no longer different from those of controls. The present study suggests that memory in patients with relatively pure cerebellar dysfunction is only partially compromised and that the impairment is secondary to a deficit in executive functions.
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Positron emission tomography measurements of regional cerebral blood flow (rCBF) were performed in normal volunteers during two auditory--verbal memory tasks: a subspan and supraspan task. The difference in rCBF between tasks was used to identify brain areas/systems involved in auditory--verbal long-term memory. Increases in rCBF were observed in the left and right prefrontal cortex, precuneus and the retrosplenial area of the cingulate gyrus. Decreases in blood flow were centred in the superior temporal gyrus bilaterally. Separate comparisons were also made between each span task and a resting state. Brain regions showing increases in rCBF in these comparisons included the thalamus, left anterior cingulate, right parahippocampal gyrus, cerebellum and the superior temporal gyrus. The brain areas identified in these comparison define a number of the neuroanatomical components of a distributed system for signal processing and storage relevant to auditory--verbal memory function.
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This study aimed at investigating the clinical usefulness of the Mental Deterioration Battery (MDB) in the neuropsychological diagnosis and characterization of the dementia syndrome. In this paper, we report: (a) normative data for various test scores derived from the analysis of performance of 340 normal subjects living in urban areas; (b) an evaluation of the reliability of the single tests and of the battery as a whole in differentiating normal subjects from patients affected by cognitive deterioration derived from the analysis of performance of 130 normal subjects living in rural areas and 134 patients affected by probable Alzheimer's dementia; (c) a cluster analysis of performances of the 340 normal subjects in the standardization group to evaluate possible criteria of homogeneity according to which the various MDB scores tend to aggregate; (d) an analysis of performance profiles of 183 patients with right monohemispheric focal lesions, 159 patients with left unilateral lesions with aphasia and 131 left-lesioned nonaphasic patients to evaluate the specificity of the single tests of the battery in documenting a selective impairment of one of the two cerebral hemispheres. Results confirm the reliability of the MBD in discriminating between normal and demented patients and provide indications for use of the battery in differentiating qualitative patterns of cognitive impairment.
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The cerebellum has been implicated in higher-order behavior. Blood flow studies (SPECT) have shown that cerebral diaschisis can appear after cerebellar lesions and this phenomenon could serve as a basis for a potential neuropsychological derangement after cerebellar insults. Our objectives in this study were to delineate the neuropsychological profile after cerebellar stroke, to evaluate cerebral diaschisis as measured by SPECT and to correlate the findings. We prospectively studied 26 patients with cerebellar stroke and 16 subjects matched for age, sex and educational level as a control group. A neuropsychological battery test, MRI and cerebral SPECT were performed in both groups. We found that cerebellar stroke results in motor control impairment and mild naming deficit, whereas no dysfunction in declarative memory, language, visuospatial or executive abilities is evident. The anatomical distribution of the lesion does not seem relevant in terms of neuropsychological impairment or diaschisis. Both ipsilateral and contralateral diaschisis as a result of a cerebellar stroke are found, but this phenomenon does not seem to result in overt neuropsychological derangement.
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The cerebellum traditionally has been viewed as a neural device dedicated to motor control. Although recent evidence shows that it is involved in nonmotor operations as well, an important question is whether this involvement is independent of motor control and motor guidance. Functional magnetic resonance imaging was used to demonstrate that attention and motor performance independently activate distinct cerebellar regions. These findings support a broader concept of cerebellar function, in which the cerebellum is involved in diverse cognitive and noncognitive neurobehavioral systems, including the attention and motor systems, in order to anticipate imminent information acquisition, analysis, or action.
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The aim of the present study was to investigate the influence of focal cerebellar lesions on procedural learning. Eight patients with cerebellar lesions and six control subjects were tested in a serial reaction-time task. A four-choice reaction-time task was employed in which the stimuli followed (or not) a sequence repeated 10 times, with the subjects aware (or not) of the item sequence. Learning was manifested by the reduction in response latency over the sequential blocks. Acquisition of declarative knowledge of the sequence was also tested. Reaction times displayed by patients with cerebellar lesions, even though they tended to be longer than those of control subjects in all testing conditions, significantly differed from control subjects only when the stimuli were presented in sequence. The reaction times in sequential trials were still statistically significant when simple motor response times were taken into account. Cerebellar patients were also significantly impaired in detecting and repeating the sequence. On the other hand, when the sequence was learned before testing, motor performances were significantly improved in all subjects. These data indicate that cerebellar lesions induce specific impairment in the procedural learning of a motor sequence and suggest a role of the cerebellar circuitry in detecting and recognizing event sequences.
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Anatomical, physiological and functional neuroimaging studies suggest that the cerebellum participates in the organization of higher order function, but there are very few descriptions of clinically relevant cases that address this possibility. We performed neurological examinations, bedside mental state tests, neuropsychological studies and anatomical neuroimaging on 20 patients with diseases confined to the cerebellum, and evaluated the nature and severity of the changes in neurological and mental function. Behavioural changes were clinically prominent in patients with lesions involving the posterior lobe of the cerebellum and the vermis, and in some cases they were the most noticeable aspects of the presentation. These changes were characterized by: impairment of executive functions such as planning, set-shifting, verbal fluency, abstract reasoning and working memory; difficulties with spatial cognition including visual-spatial organization and memory; personality change with blunting of affect or disinhibited and inappropriate behaviour; and language deficits including agrammatism and dysprosodia. Lesions of the anterior lobe of the cerebellum produced only minor changes in executive and visual-spatial functions. We have called this newly defined clinical entity the 'cerebellar cognitive affective syndrome'. The constellation of deficits is suggestive of disruption of the cerebellar modulation of neural circuits that link prefrontal, posterior parietal, superior temporal and limbic cortices with the cerebellum.
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Recent clinical and functional neuroimaging evidence points towards a cerebellar role in verbal production. At present it is not clear how the cerebellum participates in language production. The aim was to investigate the influence of cerebellar lesions on verbal fluency abilities with specific focus on the verbal searching strategies employed by patients with cerebellar damage. Twenty five patients with focal or degenerative cerebellar disease and 14 control subjects were tested in a timed verbal fluency task requiring word production under forced (phonemic or semantic) conditions. To analyse the verbal searching strategy employed, semantic and phonemic cluster analyses were also performed. Performances of cerebellar patients were comparable with those of controls in the semantic task; conversely their performances were significantly impaired when tested in the letter task. Cluster analysis results showed that the verbal fluency impairment is linked to specific damage of phonemically related retrieval strategies. Cerebellar damage impairs verbal fluency by specifically affecting phonemic rule performances while sparing semantic rule ones. These findings underline the importance of the cerebellar computing properties in strategy development in the linguistic domain.
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The cerebellum is known to project via the thalamus to multiple motor areas of the cerebral cortex. In this study, we examined the extent and anatomical organization of cerebellar input to multiple regions of prefrontal cortex. We first used conventional retrograde tracers to map the origin of thalamic projections to five prefrontal regions: medial area 9 (9m), lateral area 9 (9l), dorsal area 46 (46d), ventral area 46, and lateral area 12. Only areas 46d, 9m, and 9l received substantial input from thalamic regions included within the zone of termination of cerebellar efferents. This suggested that these cortical areas were the target of cerebellar output. We tested this possibility using retrograde transneuronal transport of the McIntyre-B strain of herpes simplex virus type 1 from areas of prefrontal cortex. Neurons labeled by retrograde transneuronal transport of virus were found in the dentate nucleus only after injections into areas 46d, 9m, and 9l. The precise location of labeled neurons in the dentate varied with the prefrontal area injected. In addition, the dentate neurons labeled after virus injections into prefrontal areas were located in regions spatially separate from those labeled after virus injections into motor areas of the cerebral cortex. Our observations indicate that the cerebellum influences several areas of prefrontal cortex via the thalamus. Furthermore, separate output channels exist in the dentate to influence motor and cognitive operations. These results provide an anatomical substrate for the cerebellum to be involved in cognitive functions such as planning, working memory, and rule-based learning.
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A 7-year-old boy developed mutism after surgery for cerebellar medulloblastoma. Postoperative magnetic resonance imaging (MRI) showed atrophy of the cerebellar vermis and both cerebellar hemispheres, predominantly on the right side. Single photon emission computed tomography (SPECT) with technetium-99m-ethyl cysteinate dimer (Tc-99m ECD) revealed decreased cerebral blood flow (CBF) in the bilateral thalami, bilateral medial frontal lobes, and left temporal lobe in addition to the cerebellar vermis and both cerebellar hemispheres when mutism was manifest, indicating the existence of bilateral crossed cerebello-cerebral diaschisis (BCCCD). Circulatory disturbance in both cerebellar hemispheres secondary to tumor resection probably caused BCCCD in both cerebral hemispheres, predominantly in the left, via the dentatothalamocortical pathway (DTCP). With recovery of his mutism, CBF increased in the right thalamus, bilateral medial frontal lobes and left temporal lobe. Thus BCCCD was improved, with only a slight decrease in CBF still persisting in the left thalamus. The mechanism of mutism may have involved damage to the cerebellar vermis (the site of incision at operation), the left dentate nucleus (heavily infiltrated by the tumor) and the right dentate nucleus of the cerebellum (affected by circulatory disturbance secondary to acute postoperative edema). The SPECT findings suggested that mutism was associated with BCCCD-induced cerebral circulatory and metabolic hypofunction in the supplementary motor area mediated via the DTCP.
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The differential role of the cerebellar cortex and nuclei has rarely been addressed in human lesion and functional brain imaging studies. One important reason is the difficulty of defining the localization of the cerebellar nuclei and extent of possible lesions based on CT or MR scans. The present MRI investigation was specifically designed to study the anatomy of the deep cerebellar nuclei. In both basal ganglia and cerebellar nuclei of healthy human subjects the amount of iron is high compared to the rest of the brain. Clusters of iron are paramagnetic and, therefore, tend to cause local inhomogenities in a magnetic field. The iron-induced susceptibility artefacts were used to visualize the cerebellar nuclei as hypointensities on MR images. A three-dimensional atlas of the dentate (D), interposed (I), and fastigial (F) nuclei is presented in standard proportional stereotaxic space coordinates based on findings in a healthy 26-year-old female. A three-dimensional axial volume of the cerebellum was acquired using a T1-weighted fast low-angle shot (FLASH) sequence on a Siemens Sonata 1.5 Tesla MR. To increase the signal to noise ratio the sequence was acquired 5 times and averaged. Each volume was registered, resampled to 1.00 x 1.00 x 1.00-mm3 voxel size and spatially normalized into a standard proportional stereotaxic space (the MNI-space) using SPM99. Localization of cerebellar nuclei were confirmed by comparison with postmortem MRI and histological microsections of another brain.
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Cerebellar involvement in spatial data management has been suggested on experimental and clinical grounds. To attempt a specific analysis of visuospatial abilities in a group of subjects with focal or atrophic cerebellar damage. Visuospatial performance was tested using the spatial subtests of the WAIS, the Benton line orientation test, and two tests of mental rotation of objects-the Minnesota paper form board test (MIN) and the differential aptitude test (DAT). In the Benton line orientation test, a test of sensory analysis and elementary perception, no deficits were present in subjects with cerebellar damage. In MIN, which analyses the capacity to process bidimensional complex figures mentally, and in the DAT, which is based on mental folding and manipulation of tridimensional stimuli, subjects with cerebellar damage were impaired. The results indicate that lesions of the cerebellar circuits affect visuospatial ability. The ability to rotate objects mentally is a possible functional substrate of the observed deficits. A comparison between visuospatial performance of subjects with focal right and left cerebellar lesions shows side differences in the characteristics of the visuospatial syndrome. Thus cerebellar influences on spatial cognition appear to act on multiple cognitive modules.
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Anatomical evidence and lesion studies, as well as functional magnetic resonance imaging (fMRI) studies, indicate that the cerebellum contributes to higher cognitive functions. Cerebellar posterior lateral regions seem to be relevant for cognition, while vermal lesions seem to be associated with changes in affect. However, the results remain controversial. Deficits of patients are sometimes still attributed to motor impairment. We present data from a detailed neuropsychological examination of 21 patients with cerebellar lesions due to tumour or haematoma, and 21 controls matched for age, sex, and years of education. Patients showed deficits in executive function, and in attentional processes such as working memory and divided attention. Further analysis revealed that patients with right-sided lesions were in general more impaired than those with left-sided lesions. Those hypotheses that suggest that lesions of the right cerebellar hemisphere lead to verbal deficits, while those of the left lead to non-verbal deficits, have in part been confirmed. The generally greater impairment of those patients with a right-sided lesion has been interpreted as resulting from the connection of the right cerebellum to the left cerebral hemisphere, which is dominant for language functions and crucial for right hand movements. Motor impairment was correlated with less than half of the cognitive measures, with no stronger tendency for correlation with cognitive tests that require motor responses discernible. The results are discussed on the basis of an assumption that the cerebellum has a predicting and preparing function, indicating that cerebellar lesions lead to a "dysmetria of thought."
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To explicate the neural correlates of sex differences in visuospatial and verbal fluency tasks, we examined behavioural performance and blood-oxygenation-level-dependent (BOLD) regional brain activity, using functional magnetic resonance imaging, during a three-dimensional (3D) mental rotation task and a compressed sequence overt verbal fluency task in a group of healthy men (n=9) and women (n=10; tested during the low-oestrogen phase of the menstrual cycle). Men outperformed women on the mental rotation task, and women outperformed men on the verbal fluency task. For the mental rotation task, men and women activated areas in the right superior parietal lobe and the bilateral middle occipital gyrus in association with the rotation condition. In addition, men activated the left middle temporal gyrus and the right angular gyrus. For verbal fluency, men activated areas in the bilateral superior frontal gyrus, right cingulate gyrus, left precentral gyrus, left medial frontal gyrus, left inferior frontal gyrus, thalamus, left parahippocampal gyrus and bilateral lingual gyrus, and women activated areas in the bilateral inferior frontal gyrus and left caudate. Despite observing task related activation in the hypothesised areas in men and women, no areas significantly differentiated the two sexes. Our results demonstrate comparable brain activation in men and women in association with mental rotation and verbal fluency function with differential performance, and provide support for sex differences in brain-behaviour relationships.
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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.
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In studies of patients with focal brain lesions, it is often useful to coregister an image of the patient's brain to that of another subject or a standard template. We refer to this process as spatial normalization. Spatial normalization can improve the presentation and analysis of lesion location in neuropsychological studies; it can also allow other data, for example from functional imaging, to be compared to data from other patients or normal controls. In functional imaging, the standard procedure for spatial normalization is to use an automated algorithm, which minimizes a measure of difference between image and template, based on image intensity values. These algorithms usually optimize both linear (translations, rotations, zooms, and shears) and nonlinear transforms. In the presence of a focal lesion, automated algorithms attempt to reduce image mismatch between template and image at the site of the lesion. This can lead to significant inappropriate image distortion, especially when nonlinear transforms are used. One solution is to use cost-function masking—masking the areas used in the calculation of image difference—to exclude the area of the lesion, so that the lesion does not bias the transformations. We introduce and evaluate this technique using normalizations of a selection of brains with focal lesions and normal brains with simulated lesions. Our results suggest that cost-function masking is superior to the standard approach to this problem, which is affine-only normalization; we propose that cost-function masking should be used routinely for normalizations of brains with focal lesions.
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4th Ed Bibliogr. na konci kapitol
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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.
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A scintigraphic single photon emission computed tomographic (SPECT) evaluation of frontal perfusion alteration was performed in five patients with known cerebellar lesions but with normal supratentorial computed tomographic (CT) or magnetic resonance (MR) scans. A clearly evident asymmetry was found in prefrontal areas in the four subjects with acquired cerebellar damage. The fifth subject, who had congenital left cerebellar hypoplasia, did not show any frontal flow asymmetry. The data support the growing clinical evidence that the cerebellum contributes to the cognitive processes of the frontal lobes and suggest a possible role for SPECT examination in the assessment of functional cognitive impairment in patients with acquired cerebellar lesions.
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We studied 12 patients with unilateral cerebellar hemorrhage to look at its effect on regional cerebral blood flow. We used single-photon emission computed tomography by continuous inhalation of xenon-133. The blood flow was quantified in the cerebellum and in nine areas of interest on the slice passing through the basal ganglia. The comparison of the blood flow values of the patients and control subjects showed a significant reduction in the contralateral hemisphere of the patients, predominantly in the frontal region and in the lenticular nucleus of the contralateral hemisphere but also in the anterointernal frontal area of the ipsilateral hemisphere. The analysis of the asymmetry indexes revealed in the same way significant differences between patients and control subjects in the frontal cortex and in the lenticular nucleus. These results provided concordant evidence suggesting a blood flow reduction in the contralateral hemisphere. This phenomenon of "crossed hemispheric diaschisis" is probably related to the interruption of cerebellocortical tracts.
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Crossed cerebellar diaschisis is a condition in which cerebellar hypometabolism is ascribed to functional disconnection of the contralateral hemisphere from the cerebral cortex. Interruption of the cerebropontine-cerebellar pathway is thought to be the most likely mechanism of this remote transneuronal metabolic depression. This phenomenon can be diagnosed by positron emission tomography, as there is hypometabolism in the affected cerebellar hemisphere. The morphologic features of the affected cerebellar hemisphere in patients with the diagnosis of crossed cerebellar diaschisis have not previously been studied by MR imaging. We retrospectively reviewed 26 patients in whom the diagnosis of crossed cerebellar diaschisis was suggested by positron emission tomography; these patients also had MR studies. In all 26 patients, supratentorial diseases were documented by MR imaging. Twenty-four of the 26 patients had a pathologic diagnosis. Detailed clinical history was also obtained for all patients. MR findings of morphologic change in the affected cerebellum were correlated with the patient's clinical symptoms and supratentorial disease. Of the 26 patients, eight had cerebellar atrophy; the remaining 18 patients showed no MR abnormality of the affected cerebellum. In the 18 in whom no atrophy was seen on MR imaging, the majority of the supratentorial lesions were tumors. The eight patients in whom cerebellar atrophy was demonstrated usually had significant contralateral supratentorial hemispheric atrophy. The patients with atrophy were also generally younger (average age, 14 years) than the 18 patients without cerebellar atrophy (average age, 42 years). Our experience shows that a significant number of patients with crossed cerebellar diaschisis have morphologic changes of cerebellar atrophy shown by MR imaging. These patients usually have significant contralateral supratentorial hemispheric atrophy.
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One hundred and twenty nine patients affected by a cerebral lesion confined to a single lobe, underwent a battery of tests including the "Temporal Rule Induction" (TRI) and the Raven's "Coloured Progressive Matrices" (CPM). Frontal patients scored lower than any other group on TRI and parietal patients on CPM. This contrasting pattern of performance provides strong empirical support to the hypothesis that the frontal lobe is specifically involved in tasks that require a control on temporally ordered information whereas the parietal lobe is concerned with cognitive activities that imply visuo-spatial analysis.
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Although the cerebellum has traditionally been regarded as a motor mechanism, recent behavioral evidence indicates that the human cerebellum is involved in a wider range of functions: in learning, in planning, in judging time, in some emotional and cognitive disorders such as autism, and in some normal mental activities such as the cognitive processing of words. This evidence suggests that the traditional view of cerebellar function now needs to be reassessed and enlarged to include nonmotor as well as motor functions in the human brain. Whereas the cerebellar connections to frontal motor areas enable the cerebellum to improve motor skills, cerebellar connections to adjacent association areas of the prefrontal cortex can enable the cerebellum to improve mental skills, and cerebellar connections to Broca's area can enable the cerebellum to improve language skills.
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Short-term and long-term retention of experimentally presented words were compared in a sample of 33 healthy normal volunteers by the [15O]H2O method with positron emission tomography (PET). The design included three conditions. For the long-term condition, subjects thoroughly studied 18 words 1 week before the PET study. For the short-term condition, subjects were shown another set of 18 words 60 sec before imaging, with instructions to remember them. For the baseline condition, subtracted from the two memory conditions, subjects read a third set of words that they had not previously seen in the experiment. Similar regions were activated in both short-term and long-term conditions: large right frontal areas, biparietal areas, and the left cerebellum. In addition, the short-term condition also activated a relatively large region in the left prefrontal region. These complex distributed circuits appear to represent the neural substrates for aspects of memory such as encoding, retrieval, and storage. They indicate that circuitry involved in episodic memory has much larger cortical and cerebellar components than has been emphasized in earlier lesion studies.
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Magnetic resonance imaging was used to examine the involvement of the dentate nucleus of the cerebellum in cognitive operations. All seven people examined displayed a large bilateral activation in the dentate during their attempts to solve a pegboard puzzle. The area activated was three to four times greater than that activated during simple movements of the pegs. These results provide support for the concept that the computational power of the cerebellum is applied not only to the control of movement but also to cognitive functions.
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Four patients with clinical signs of cerebellar stroke were studied twice by SPECT using 99mTc-HMPAO as a tracer for cerebral blood flow (CBF). When first scanned 6 to 22 days after onset, all had a region of very low CBF in the symptomatic cerebellar hemisphere, and a mild to moderate CBF reduction (average 10%) in contralateral hemispheric cortex. In all four cases clinical signs of unilateral cerebellar dysfunction were still present when rescanned 1 to 4 months later and the relative CBF decrease in the contralateral cortex of the forebrain also remained. The basal ganglia contralateral to the cerebellar lesion CBF showed variable alterations. A relative CBF decrease was seen in upper part of basal ganglia in all four cases, but it was not a constant phenomenon. A relative CBF increase in both early and late SPECT scans was seen at low levels of neostriatum in two cases. The remote CBF changes in cerebellar stroke seen in the forebrain are probably caused by reduced or abolished cerebellar output. The term "Crossed Cerebral Diaschisis" may be used to describe these CBF changes that would appear to reflect both decreased and increased neuronal activity.
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In 1914, Von Monakow described diaschisis, the recovery of lost cortical function in regions positionally distant from, but linked by neuronal tracts to, the primary site of cortical damage. Cerebellar diaschisis after cortical insult is detailed in the literature; however, cortical diaschisis after cerebellar insult remains a rarely reported occurrence. We describe a 36-year-old woman with rupture of a right-sided cerebellar arteriovenous malformation who developed such expected cerebellar signs as ataxia, dysmetria, and nystagmus. Days later, the patient developed profound impulsivity, disinhibition, and psychomotor agitation. Single photon emission computed tomography (SPECT) showed decreased perfusion of the bilateral frontal and temporal lobes, consistent with regional loss of neural activity. Eventual clinical improvement corresponded with reperfusion of those regions, identified on follow-up SPECT. This case documents cortical diaschisis following cerebellar insult and shows that diaschisis must be considered in patients with cerebral injury manifesting cortical deficits remote from the site of primary pathology.
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If there is a cerebellar contribution to nonmotor function, particularly to cognitive abilities and affective states, then there must be corresponding anatomic substrates that support this. The cerebellum is strongly interconnected with the cerebral hemispheres in both feedforward (cerebral hemispheres to cerebellum) and feedback directions. This relationship has long been recognized, particularly with respect to the motor and sensory cortices. Investigations performed over the last decade however, have demonstrated for the first time the organization and strength of the connections that link the cerebellum with areas of the cerebral cortex known to be concerned with higher order behavior rather than with motor control. The feedforward projections from these higher order areas, namely the associative and paralimbic cortices, seem to be matched, at least in the limited but definite demonstrations to date, by cerebellar projections back to these same areas. These observations are important because they are congruent with the notion that cognitive functions are distributed among multiple cortical and subcortical nodes, each of which functions in concert but in a unique manner to produce an ultimate behavior pattern. This chapter describes the neural circuitry postulated to subserve the cerebellar contribution to nonmotor processing, particularly cognitive and affective modulation, and discusses the theoretical implications of these anatomic findings.
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New neuroimaging studies provide striking evidence that the cerebellum is intensely and selectively active during sensory and cognitive tasks, even in the absence of explicit or implicit motor behavior. Focal activity is observed in the lateral cerebellar hemispheres during the processing of auditory, visual, cutaneous, spatial, and tactile information, and in anterior-medial cerebellar regions during somatomotor behavior. Moreover, a double dissociation exists between (a) cerebellar activity and sensory processing and (b) motor behavior and activity in known motor areas in the cerebral cortex. These findings contradict the classical motor coordination theory of cerebellar function but are predicted by, or are at least consistent with, new alternative theories.
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We investigated the risk factors for silent lacunar infarction and etat criblé detected by magnetic resonance imaging (MRI). Previous reports have evaluated white matter hyperintensities (WMHs) and periventricular hyperintensities (PVHs) on T2-weighted images, but have not distinguished between lacunar infarcts, état criblé, and leukoaraiosis of Binswanger's type. MRI scans were performed in 270 subjects without neurological deficits over the age of 40 years. They were classified into four subtype groups based on MR findings: normal group (n =60), état criblé group (n=69), silent lacunar infarct/PVH(-) group (n=61), and silent lacunar infarct/PVH(+) group (n=80). We examined the following biochemical variables and other potential risk factors by ordinary logistic regression analysis to identify independent and significant risk factors for silent lacunar infarction: serum levels of total cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, lipoprotein(a), HbA1c, age, sex, systolic blood pressure, diastolic blood pressure, duration of hypertension, family history, smoking habits, alcohol intake, obesity (body mass index), and atrial fibrillation. Subjects in the silent lacunar infarct/PVH(-) (P<0.01) and PVH(+) (P<0.001) groups were significantly older than normal subjects. The systolic blood pressure was also significantly higher in the silent lacunar infarct/PVH(-) (P<0.04) and PVH(+) (P<0.01) groups compared with the normal group. The duration of hypertension was significantly longer in the silent lacunar infarct/PVH(+) group (P<0.02). There were no significant differences in other risk factors between the normal group and the other groups. Ordinary logistic regression analysis showed that age (chi-square 51.8, P<0.0001) and systolic blood pressure (chi-square 5.7, P<0.02) were significant and independent risk factors for silent lacunar infarction. Aging and hypertension were shown to be independent risk factors for silent lacunar infarction.
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The pathophysiology of crossed cerebellar diaschisis (CCD) remains to be elucidated. In CCD, the metabolic suppression resulting from deafferentation may cause vasoconstriction, which may result in a decrease in cerebral blood volume (CBV) and may differentially affect the flows of red blood cells and of plasma. The purpose of this study was to investigate whether CCD decreases the total CBV (cerebral red blood cell volume [CRCV] plus cerebral plasma volume [CPV]) and, if so, whether CCD differentially affects the CRCV and CPV, resulting in a change in hematocrit. We used positron emission tomography to study 7 patients with a unilateral supratentorial infarct and CCD. The distributions of CRCV and CPV were assessed by using 15O-labeled carbon monoxide and 62Cu-labeled human serum albumin-dithiosemicarbazone tracers, respectively. The CRCV, CPV, and calculated hematocrit values were compared between the cerebellar hemispheres. In the cerebellar cortex contralateral to the supratentorial infarct, the values of CRCV, CPV, and total CBV were significantly decreased compared with those in the ipsilateral cerebellar cortex. The CRCV was decreased to a greater degree than the CPV, and the value of the hematocrit was decreased in the contralateral cerebellar cortex. CCD may decrease the total CBV, which may reflect vasoconstriction caused by decreased metabolism due to deafferentation. In addition, the more pronounced decrease in CRCV than in CPV may result in a decrease in hematocrit in CCD.
Article
The pathophysiology of deafferentation-induced changes after stroke remains unclear. Some supratentorial strokes cause persistent decreases in blood flow and metabolism in the contralateral cerebellum (persistent crossed cerebellar diaschisis[CCD]). Our previous study showed uncoupling of oxygen consumption and blood flow in this condition, which may reflect a characteristic change in brain metabolism caused by deafferentation. This uncoupling might be related to oxidation of some substrates other than blood-borne glucose, which could also lead to the uncoupling of oxygen consumption and glucose utilization. The purpose of this study was to investigate whether oxygen consumption is uncoupled from glucose utilization in persistent CCD. Using positron emission tomography in 10 unilateral supratentorial stroke patients, we evaluated regional blood flow, oxygen consumption, and glucose utilization in the cerebellar cortex in the chronic stage. Eight patients with a significant cerebellar blood flow asymmetry, defined as outside the 95% confidence limits predefined in 9 normal subjects, were selected as patients with persistent CCD. In patients with CCD, the cerebellar cortex contralateral to the stroke showed significant decreases in both oxygen consumption and glucose utilization compared with the ipsilateral cerebellar cortex. The decrease in oxygen consumption was less than the decrease in glucose utilization, resulting in a significant increase in the oxygen consumption/glucose utilization ratio. Persistent CCD caused by stroke may induce uncoupling of oxygen consumption and glucose utilization, which may reflect a characteristic change in brain metabolism caused by deafferentation.
Article
We performed single-photon emission computed tomography (SPECT) to investigate crossed cerebellocerebral diaschisis (CCCD) in patients with cerebellar stroke. Fifteen patients with unilateral cerebellar stroke underwent SPECT of the brain with N-isopropyl-p-[123I] iodoamphetamine (123I-IMP). Regional cerebral blood flow (rCBF) was measured by the autoradiographic method. Regions of interest were defined in the cerebral cortex, striatum, thalamus and cerebellum to compare structures (contralateral to the cerebellar lesion) with counterparts ipsilateral to the stroke. In the frontal and parietal cortices, especially the posterior superior frontal, anterior midfrontal, precentral, postcentral, and supramarginal areas, rCBF contralateral to the lesion was significantly lower than on the side of the lesion (showing CCCD). This CCCD phenomenon is important to be aware of in clinical reading of images.
Article
We present data on the intellectual, language and executive functions of 26 children who had undergone surgery for the removal of cerebellar hemisphere or vermal tumours. The children with right cerebellar tumours presented with disturbances of auditory sequential memory and language processing, whereas those with left cerebellar tumours showed deficits on tests of spatial and visual sequential memory. The vermal lesions led to two profiles: (i) post-surgical mutism, which evolved into speech disorders or language disturbances similar to agrammatism; and (ii) behavioural disturbances ranging from irritability to behaviours reminiscent of autism. These data are consistent with the recently acknowledged role of the cerebellum as a modulator of mental and social functions, and suggest that this role is operative early in childhood.
Article
Relatively few data exist concerning functional recovery after ischemic and hemorrhagic cerebellar stroke. We studied patients admitted to a rehabilitation hospital after cerebellar stroke to quantify recovery after rehabilitation therapy and to identify variables that predicted functional outcome. This study was a retrospective review of consecutive cases admitted in a 4-year period with new cerebellar infarct or hemorrhage. Clinical features of stroke were recorded and comorbidities scored with the Charlson Index. Follow-up information was obtained by telephone interview. The Functional Independence Measure (FIM) was scored at admission (AFIM), discharge (DFIM), and follow-up (FFIM). Outcome measures were DFIM and FFIM. Univariate and multivariate analyses were performed. Fifty-eight cases were identified (mean age 69.2 years; 49 infarcts, 9 hemorrhages). Mean AFIM was 65.5, and mean DFIM was 89.8. Mean AFIM was significantly higher in the infarct than in the hemorrhage subgroup (70 versus 43, P:=0.006). Mean DFIM was also higher in the infarct subgroup but did not reach statistical significance (93 versus 74, P:=0.1). Follow-up information was obtained for 45 cases (78%) (mean interval 19.5 months). Median FFIM was 123.5. Outcome was significantly positively correlated with AFIM and initial presenting syndrome of vertigo/vomiting/ataxia/headache. Outcome correlated negatively with preexisting comorbidity score, altered level of consciousness at initial presentation, and superior cerebellar artery infarction. On multivariate analysis, AFIM and comorbidity score were independent predictors of outcome. Substantial improvement of mean FIM score frequently occurs after rehabilitation after cerebellar infarction. Functional outcome is best predicted by preexisting comorbidities and functional status at the time of discharge from acute hospitalization.
Article
The comprehension of the cerebellar physiology is rapidly changing in particular because of the demonstration of the cerebellar importance on cognition. In the present paper, recent data on cerebro cerebellar interactions is reviewed, particularly focusing on cerebellar influences over the neurophysiology of primary motor and primary sensory cortices. The cerebellar role in implicit learning and in sensory data processing is analysed and discussed. It is proposed that the cerebellum could control cortical plastic changes by modulating cortical excitability in a discrete topographic manner and that this mechanism could induce the coupling between significant sensory inputs and definite motor outputs considered as the neurobiological substrate for implicit learning.
Article
In three patients with infantile hemiplegia syndrome, MR imaging done later in life showed significant volume loss in the cerebellar hemisphere contralateral to the side of the affected cerebrum in two and ipsilateral in one. By comparison, the cerebellar volume loss seemed to correlate with the degree of volume loss in the contralateral cerebral hemispheres in two patients. These observations provide morphological evidence of the phenomenon of crossed and uncrossed/ipsilateral cerebral cerebellar diaschisis (CCD and ICD). Functional neuroimaging studies in support of the concept of CCD and ICD have been critically reviewed in the light of the morphological changes demonstrated in the cases cited herein.
Article
Mapping of cerebellar function by functional MRI now enables us not only to re-establish older anatomic findings of somatotopic representations but to gain new insights in the function of the cerebellum and its intimate relations of cerebral regions to serving sensorimotor function, sensory discrimination, and cognitive processing. Consequently, it will change our understanding of neurologic and psychologic failures in patients with inborn errors or neurodegenerative diseases or after neurosurgical procedures.
Article
Converging evidence has implicated the cerebellum in verbal working memory. The current fMRI study sought to further characterize cerebrocerebellar participation in this cognitive process by revealing regions of activation common to a verbal working task and an articulatory control task, as well as regions that are uniquely activated by working memory. Consistent with our model's predictions, load-dependent activations were observed in Broca's area (BA 44/6) and the superior cerebellar hemisphere (VI/CrusI) for both working memory and motoric rehearsal. In contrast, activations unique to verbal working memory were found in the inferior parietal lobule (BA 40) and the right inferior cerebellum hemisphere (VIIB). These findings provide evidence for two cerebrocerebellar networks for verbal working memory: a frontal/superior cerebellar articulatory control system and a parietal/inferior cerebellar phonological storage system.
Article
The aim of the present study was to verify the hypothesis advanced by Hécaen and Assal (1970), that the presence of landmarks can improve the copying performance of left brain-damaged patients, while leaving unchanged that of right brain-damaged patients. Sixty-two control subjects and 196 brain-damaged patients with lesions restricted to the right (N = 84) or to the left (N = 112) cerebral hemisphere were given two tests of copying drawings. In the first task the patients were asked to directly copy a drawing; to perform the second test they were given guiding landmarks. On both tests no difference was found between the performance of the two hemispheric groups. Right-sided patients used a lower number of guiding landmarks, but this occurred only on the half of the drawings contralateral to the side of the lesion and was apparently due to unilateral spatial neglect.
Article
The role of the cerebellum in cognitive functions has been under debate. We investigated the neuropsychological functioning of patients with cerebellar lesions (infarcts) and evaluated the significance of laterality in cognitive symptoms. Twenty-six patients with exclusive cerebellar lesions as verified by clinical and neuroradiological findings underwent a neuropsychological assessment at the acute stage and at 3 months. Their performance was compared with 14 controls, also assessed twice. The focus was on four domains: visuospatial/motor functions, episodic memory, working memory and attentional shifting/execution. Both groups improved over time. Statistical differences emerged in tests in the visuomotor domain as well as in the episodic and working memory domains. Patients with left cerebellar lesion were slow in a visuospatial task, whereas those with right cerebellar lesions had verbal memory difficulty compared with controls. By 3 months, 77% of the patients had returned to work, and only one had cognitive impairment and did not return to work. Our results indicate that cerebellar infarcts may result in subtle cognitive changes perhaps primarily related to working memory deficit. The symptoms may be mediated by the contralateral cortical hemisphere, left cerebellar infarcts producing mild right hemispheral dysfunction and right cerebellar infarct producing mild left hemispheral dysfunction.