Evidence for distinct cognitive deficits after focal cerebellar lesions

OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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."     

Cerebellar involvement in executive control

The cerebellum has long been considered to be mainly involved in motor function. In the last 20 years, evidence from neuroimaging studies and from investigations of patients with cerebellar lesions has shown that the cerebellum plays a role in a range of cognitive functions. While cerebellar contributions have been shown for learning and memory, the cerebellum has also been linked to higher order cognitive control processes frequently referred to as executive functions. Although it is widely accepted that the cerebellum contributes to cognitive processing, the nature of cerebellar involvement is not well understood. The present paper focuses on the role of the cerebellum in executive processing, reviewing findings derived from neuroimaging studies or from studies investigating deficits related to cerebellar dysfunction. As executive functions cannot be considered as a unitary concept, special emphasis is put on cerebellar contributions to different aspects of executive control such as working memory, multitasking or inhibition. Referring to models derived from motor control, possible mechanisms of cerebellar involvement in executive processing are discussed. Finally, methodological problems in assessing executive deficits in general and in assessing the cerebellar contribution to executive processing in particular are addressed.     

Surgery of tumors of the cerebellum and prefrontal cortex, and sensory memory and motor planning disturbances in children

OBJECT: This study addressed the integration of sensory short-term memory (SSTM) and motor planning (MP) in the lateral cerebellar region, where the dentate nucleus is localized, and in the prefrontal cortex (PF). METHODS: Boucher and Lewis's test of SSTM and MP was administered pre- and postsurgically to 8 patients of either sex, between 5 and 19 years of age, with tumors of the cerebellum, PF (area 9 medial) or the parieto-occipital region, and on one occasion to 8 corresponding controls. RESULTS: Whereas lesions of the midline portions of the cerebellum and of the parietal-occipital region did not appear to cause any cognitive defects, patients with lesions affecting either the lateral cerebellar region or PF exhibited statistically significant deficits of SSTM and MP. CONCLUSIONS: The lateral cerebellum seems to act in concert with PF to integrate different cognitive activities related to holding objects in SSTM and planning motor strategies in reference to them.     

The developmental relationship between specific cognitive domains and grey matter in the cerebellum

There is growing evidence that the cerebellum is involved in cognition and cognitive development, yet little is known about the developmental relationship between cerebellar structure and cognitive subdomains in children. We used voxel-based morphometry to assess the relationship between cerebellar grey matter (GM) and language, reading, working memory, executive function, and processing speed in 110 individuals aged 8–17 years from the Pediatric Imaging, Neurocognition, and Genetics (PING) Study. Further, we examined the effect of age on the relationships between cerebellar GM and cognition. Higher scores on vocabulary, reading, working memory, and set-shifting were associated with increased GM in the posterior cerebellum (lobules VI–IX), in regions which are typically engaged during cognitive tasks in healthy adults. For reading, working memory, and processing speed, the relationship between cerebellar GM and cognitive performance changed with age in specific cerebellar subregions. As in adults, posterior lobe cerebellar GM was associated with cognitive performance in a pediatric population, and this relationship mirrored the known developmental trajectory of posterior cerebellar GM. These findings provide further evidence that specific regions of the cerebellum support cognition and cognitive development, and suggest that the strength of this relationship depends on developmental stage.     

Posterior fossa decompression and the cerebellum in Chiari type II malformation: a preliminary MRI study

Objectives  

Chiari type II malformation (CII) is a congenital deformity of the hindbrain. The posterior fossa and cerebellum are small in CII. The cerebellar atrophy is associated with cognitive and motor deficits. Brainstem compression occurs in some patients with CII for whom posterior fossa decompression may be life saving. The aim was to determine whether posterior fossa decompression can prevent or reduce the cerebellar atrophy in CII.     

Disorders of the cerebellum: ataxia, dysmetria of thought, and the cerebellar cognitive affective syndrome

Many diseases involve the cerebellum and produce ataxia, which is characterized by incoordination of balance, gait, extremity and eye movements, and dysarthria. Cerebellar lesions do not always manifest with ataxic motor syndromes, however. The cerebellar cognitive affective syndrome (CCAS) includes impairments in executive, visual-spatial, and linguistic abilities, with affective disturbance ranging from emotional blunting and depression, to disinhibition and psychotic features. The cognitive and psychiatric components of the CCAS, together with the ataxic motor disability of cerebellar disorders, are conceptualized within the dysmetria of thought hypothesis. This concept holds that a universal cerebellar transform facilitates automatic modulation of behavior around a homeostatic baseline, and the behavior being modulated is determined by the specificity of anatomic subcircuits, or loops, within the cerebrocerebellar system. Damage to the cerebellar component of the distributed neural circuit subserving sensorimotor, cognitive, and emotional processing disrupts the universal cerebellar transform, leading to the universal cerebellar impairment affecting the lesioned domain. The universal cerebellar impairment manifests as ataxia when the sensorimotor cerebellum is involved and as the CCAS when pathology is in the lateral hemisphere of the posterior cerebellum (involved in cognitive processing) or in the vermis (limbic cerebellum). Cognitive and emotional disorders may accompany cerebellar diseases or be their principal clinical presentation, and this has significance for the diagnosis and management of patients with cerebellar dysfunction.     

Cerebellar contributions to verbal working memory: beyond cognitive theory

Neuropsychological findings together with recent advances in neuroanatomical and neuroimaging techniques have spurred the investigation of cerebellar contributions to cognition. One cognitive process that has been the focus of much research is working memory, in particular its verbal component. Influenced by Baddeley’s cognitive theory of working memory, cerebellar activation during verbal working memory tasks has been predominantly attributed to the cerebellum’s involvement in an articulatory rehearsal network. Recent neuroimaging and neuropsychological findings are inconsistent with a simple motor view of the cerebellum’s function in verbal working memory. The present article examines these findings and their implications for an articulatory rehearsal proposal of cerebellar function. Moving beyond cognitive theory, we propose two alternative explanations for cerebellar involvement in verbal working memory: Error-driven adjustment and internal timing. These general theories of cerebellar function have been successfully adapted from the motor literature to explain cognitive functions of the cerebellum. We argue that these theories may also provide a useful framework to understand the non-motor contributions of the cerebellum to verbal working memory.     

Neurodevelopmental and Psychiatric Symptoms in Patients with a Cyst Compressing the Cerebellum: an Ongoing Enigma

A patient diagnosed with developmental delay, intellectual disability, and autistic and obsessive-compulsive symptoms was found to have a posterior fossa arachnoid cyst (PFAC) compressing the cerebellum. The patient was referred to our Ataxia Unit for consideration of surgical drainage of the cyst to improve his clinical constellation. This scenario led to an in-depth analysis including a literature review, functional resting-state MRI analysis of our patient compared to a group of controls, and genetic testing. While it is reasonable to consider that there may be a causal relationship between PFAC and neurodevelopmental or psychiatric symptoms in some patients, there is also a nontrivial prevalence of PFAC in the asymptomatic population and a significant possibility that many PFAC are incidental findings in the context of primary cognitive or psychiatric symptoms. Our functional MRI analysis is the first to examine brain function, and to report cerebellar dysfunction, in a patient presenting with cognitive/psychiatric symptoms found to have a structural abnormality compressing the cerebellum. These neuroimaging findings are inherently limited due to their correlational nature but provide unprecedented evidence suggesting that cerebellar compression may be associated with cerebellar dysfunction. Exome gene sequencing revealed additional etiological possibilities, highlighting the complexity of this field of cerebellar clinical and scientific practice. Our findings and discussion may guide future investigations addressing an important knowledge gap—namely, is there a link between cerebellar compression (including arachnoid cysts and possibly other forms of cerebellar compression such as Chiari malformation), cerebellar dysfunction (including fMRI abnormalities reported here), and neuropsychiatric symptoms?     

Cerebellar contributions to cognitive functions: A progress report after two decades of research

Accumulating evidence from both human lesion and functional neuroimaging studies appears to support the hypothesis that the cerebellum contributes to non-motor functions. Along similar lines, cognitive, affective and behavioural changes in psychiatric disorders, such as autism, schizophrenia and dyslexia, have been linked to structural cerebellar abnormalities. The aim of this special issue was to evaluate the current knowledge base after more than 20 years of controversial discussion. The contributions of the special issue cover the most important cognitive domains, i.e., attention, memory and learning, executive control, language and visuospatial function. The available empirical evidence suggests that cognitive changes in patients with cerebellar dysfunction are mild and clearly less severe than the impairments observed after lesions to neocortical areas to which the cerebellum is closely connected via different cerebro-cerebellar loops. Frequently cited early findings, e.g., with respect to a specific cerebellar involvement in attention, have not been replicated or might be confounded by motor or working memory demands of the respective attention task. On the other hand, there is now convincing evidence for a cerebellar involvement in the mediation of a range of cognitive domains, most notably verbal working memory. Verbal working memory problems may partly underlie the compromised performance of cerebellar lesion patients on at least some complex cognitive tasks. Although investigations have moved from anecdotical case reports to hypothesis-driven controlled clinical group studies based on sound methods which are complemented by state-of-the-art functional neuroimaging studies, the empirical evidence available so far does not yet allow a convincing theory of the mechanisms of a cerebellar involvement in cognitive function. Future studies are clearly needed to further elucidate the nature of the processes linked to cerebellar mediation of cognitive processes and their possible link to motor theories of cerebellar function, e.g., its role in prediction and/or timing.     

Cognitive and social cognitive functioning in spinocerebellar ataxia

Introduction The spinocerebellar ataxias (SCAs), are rare neurodegenerative disorders caused by distinct genetic mutations. Clinically, the SCAs are characterised by progressive ataxia and a variety of other features, including cognitive dysfunction. The latter is consistent with a growing body of evidence supporting a cognitive as well as motor role for the cerebellum. Recent suggestions of cerebellar involvement in social cognition have not been extensively explored in these conditions. The availability of definitive molecular diagnosis allows genetically defined subgroups of SCA patients, with distinct patterns of cerebellar and extracerebellar involvement, to be tested comparatively using a common battery of tests of general, social and emotional cognition. Methods: Nine patients with SCA6, and 6 with SCA3 were assessed using a comprehensive battery of neuropsychological instruments, encompassing domains of memory, language, visuo-spatial skills, calculation, attention and executive function, emotional processing and theory of mind (ToM). Results There were no deficits in visuo-spatial processing or calculation in either group, while individuals with naming and attentional difficulties were seen in both. Deficits in memory and executive function were present in both conditions, albeit more pronounced in SCA3. By contrast, both groups demonstrated consistently poor performance on ToM tests, and normal attribution of social and emotional responses. Conclusion The data support the hypothesis that the cerebellum is important for cognitive as well as motor activity. The pattern of overlap of domain impairments provides tentative preliminary evidence that there is a cerebellar contribution to aspects of memory and executive function and ToM, and that other domains depend more on neural system outside the cerebellum. The findings relating to ToM are relevant to the possibility of cerebellar involvement in autism.     

Crossed cerebro-cerebellar language dominance

In addition to its traditional role in motor control, the cerebellum has been implicated in various cognitive and linguistic functions. Lesion, anatomic, and functional imaging studies indicate a link between left frontal language regions and the right cerebellum. To probe the specificity of this circuit, we examined the association between language-related lateralized activation of the frontal cortex with lateralized activation of the cerebellum. Functional magnetic resonance imaging (fMRI) was carried out during letter-cued word generation in 14 healthy subjects: 7 subjects displayed typical left-hemisphere and 7 subjects displayed atypical right-hemisphere language dominance. We found activation of the cerebellar hemisphere contralateral to the language-dominant cerebral hemisphere in each subject. The cerebellar activation was confined to the lateral posterior cerebellar hemisphere (lobule VI, VII B, Cr I, Cr II). This study demonstrates that crossed cerebral and cerebellar language dominance is a typical characteristic of brain organization. The functional significance of the reported activations can now be tested in patients with lesions of the lateral posterior cerebellum.     

Cerebellar neurocognition: insights into the bottom of the brain

The traditional view on the core functions of the cerebellum consists of the regulation of motor coordination, balance and motor speech. However, during the past decades results from neuroanatomical, neuroimaging and clinical studies have substantially extended the functional role of the cerebellum to cognitive and affective regulation. Neuroanatomical studies convincingly showed cerebellar connectivity with associative areas of the cerebral cortex involved in higher cognitive functioning, while functional neuroimaging provided evidence of cerebellar activation during a variety of cognitive tasks. In addition, more systematic neuropsychological research performed in patients with cerebellar lesions and the development of more sensitive neuropsychological tests allowed clinicians to identify significant cognitive and affective disturbances following cerebellar damage. In this review, an overview is presented of the cerebellar role in a variety of cognitive processes, such as executive functioning, memory, learning, attention, visuo-spatial regulation, language and behavioral-affective modulation. In addition, recent evidence with regard to cerebellar induced clinical entities such as the cerebellar cognitive affective syndrome (CCAS) and the posterior fossa syndrome (PFS), will be discussed. Although extensive research has substantially broadened the insights in the cognitive and affective role of the cerebellum, the precise nature of the cerebellar contribution to cognitive and affective regulation is not yet clear. In this review experimental and clinical data will be discussed that substantiate the presumed neurobiological mechanisms underlying the cognitive and affective modulatory role of the cerebellum.     

Structural cerebellar correlates of cognitive functions in spinocerebellar ataxia type 2

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.     

Preoperative and postoperative analysis of visual and auditory memory in children with cerebellar tumors

Motivated by the extensive clinical and experimental evidence that links the cerebellum to cognitive processes, we analyzed the auditory and visual memory of nine children with cerebellar tumors. Five patients had midline lesions and four had cerebellar hemispheric tumors. The patients were tested before and after surgery. One of the patients was also tested at 4 and 24 months after surgery. A third group constituted by four children, sibling of some of the patients, served as control. Statistically significant differences (P< 0.05) were found in the test of auditory memory, in which children with cerebellar tumors made a higher number of errors than their normal counterparts. Surgery performed according standard techniques did not increase significantly the number of errors in any of the tested categories. Location of the tumor (hemispheric vs midline) was not a determinant of the performance of the children. The patient tested up to 2 years after surgery demonstrated a progressive improvement in the performance of visual and auditory memory tasks. Our results provide further evidence that the cerebellum plays a role in the integration of auditory stimuli.     

Cerebellar Transcranial Direct Current Stimulation Modulates Verbal Working Memory

BackgroundNeuroimaging studies show cerebellar activations in a wide range of cognitive tasks and patients with cerebellar lesions often present cognitive deficits suggesting a cerebellar role in higher-order cognition.ObjectiveWe used cathodal transcranial direct current stimulation (tDCS), known to inhibit neuronal excitability, over the cerebellum to investigate if cathodal tDCS impairs verbal working memory, an important higher-order cognitive faculty.MethodWe tested verbal working memory as measured by forward and backward digit spans in 40 healthy young participants before and after applying cathodal tDCS (2 mA, stimulation duration 25 min) to the right cerebellum using a randomized, sham-controlled, double-blind, cross-over design. In addition, we tested the effect of cerebellar tDCS on word reading, finger tapping and a visually cued sensorimotor task.ResultsIn line with lower digit spans in patients with cerebellar lesions, cerebellar tDCS reduced forward digit spans and blocked the practice dependent increase in backward digit spans. No effects of tDCS on word reading, finger tapping or the visually cued sensorimotor task were found.ConclusionOur results support the view that the cerebellum contributes to verbal working memory as measured by forward and backward digit spans. Moreover, the induction of reversible “virtual cerebellar lesions” in healthy individuals by means of tDCS may improve our understanding of the mechanistic basis of verbal working memory deficits in patients with cerebellar lesions.     

Frontal Lobe and Posterior Parietal Contributions to the Cortico-cerebellar System

Our growing understanding of how cerebral cortical areas communicate with the cerebellum in primates has enriched our understanding of the data that cerebellar circuits can access, and the neocortical areas that cerebellar activity can influence. The cerebellum is part of some large-scale networks involving several parts of the neocortex including association areas in the frontal lobe and the posterior parietal cortex that are known for their contributions to higher cognitive function. Understanding their connections with the cerebellum informs the debates around the role of the cerebellum in higher cognitive functions because they provide mechanisms through which association areas and the cerebellum can influence each others' operations. In recent years, evidence from connectional anatomy and human neuroimaging have comprehensively overturned the view that the cerebellum contributes only to motor control. The aim of this review is to examine our changing perspectives on the nature of cortico-cerebellar anatomy and the ways in which it continues to shape our views on its contributions to function. The review considers the anatomical connectivity of the cerebellar cortex with frontal lobe areas and the posterior parietal cortex. It will first focus on the anatomical organisation of these circuits in non-human primates before discussing new findings about this system in the human brain. It has been suggested that in non-human primates "although there is a modest input from medial prefrontal cortex, there is very little or none from the more lateral prefrontal areas" [33]. This review discusses anatomical investigations that challenge this claim. It also attempts to dispel the misconception that prefrontal projections to the cerebellum are from areas concerned only with the kinematic control of eye movements. Finally, I argue that our revised understanding of anatomy compels us to reconsider conventional views of how these systems operate in the human brain.     

Evidence for topographic organization in the cerebellum of motor control versus cognitive and affective processing

Patients with cerebellar damage often present with the cerebellar motor syndrome of dysmetria, dysarthria and ataxia, yet cerebellar lesions can also result in the cerebellar cognitive affective syndrome (CCAS), including executive, visual spatial, and linguistic impairments, and affective dysregulation. We have hypothesized that there is topographic organization in the human cerebellum such that the anterior lobe and lobule VIII contain the representation of the sensorimotor cerebellum; lobules VI and VII of the posterior lobe comprise the cognitive cerebellum; and the posterior vermis is the anatomical substrate of the limbic cerebellum. Here we analyze anatomical, functional neuroimaging, and clinical data to test this hypothesis. We find converging lines of evidence supporting regional organization of motor, cognitive, and limbic behaviors in the cerebellum. The cerebellar motor syndrome results when lesions involve the anterior lobe and parts of lobule VI, interrupting cerebellar communication with cerebral and spinal motor systems. Cognitive impairments occur when posterior lobe lesions affect lobules VI and VII (including Crus I, Crus II, and lobule VIIB), disrupting cerebellar modulation of cognitive loops with cerebral association cortices. Neuropsychiatric disorders manifest when vermis lesions deprive cerebro-cerebellar-limbic loops of cerebellar input. We consider this functional topography to be a consequence of the differential arrangement of connections of the cerebellum with the spinal cord, brainstem, and cerebral hemispheres, reflecting cerebellar incorporation into the distributed neural circuits subserving movement, cognition, and emotion. These observations provide testable hypotheses for future investigations.     

Overweight and obesity are associated with neuronal injury in the human cerebellum and hippocampus in young adults: a combined MRI,serum marker and gene expression study

There is growing evidence that obesity represents a risk for enhanced gray matter (GM) density changes comparable to those demonstrated for mild cognitive impairment in the elderly. However, it is not clear what mechanisms underlie this apparent alteration in brain structure of overweight subjects and to what extent these changes can already occur in the adolescent human brain. In the present volumetric magnetic resonance imaging study, we investigated GM changes and serum levels of neuron-specific enolase (NSE), a marker for neuronal injury, in a set of overweight/obese subjects and controls. We report a negative correlation for overweight and obese subjects between serum NSE and GM density in hippocampal and cerebellar regions. To validate our neuroimaging findings, we complement these data with NSE gene expression information obtained from the Allen Brain atlas. GM density changes were localized in brain areas that mediate cognitive function—the hippocampus associated with memory performance, and the cognitive cerebellum (lateral posterior lobes) associated with executive, spatial and linguistic processing. The data of our present study highlight the importance of extending current research on cognitive function and brain plasticity in the elderly in the context of obesity to young adult subjects and include serum biomarkers to validate imaging findings generally.     

Relationships Between Regional Cerebellar Volume and Sensorimotor and Cognitive Function in Young and Older Adults

The cerebellum has been implicated in both sensorimotor and cognitive function, but is known to undergo volumetric declines with advanced age. Individual differences in regional cerebellar volume may therefore provide insight into performance variability across the lifespan, as has been shown with other brain structures and behaviors. Here, we investigated whether there are regional age differences in cerebellar volume in young and older adults, and whether these volumes explain, in part, individual differences in sensorimotor and cognitive task performance. We found that older adults had smaller cerebellar volume than young adults; specifically, lobules in the anterior cerebellum were more impacted by age. Multiple regression analyses for both age groups revealed associations between sensorimotor task performance in several domains (balance, choice reaction time, and timing) and regional cerebellar volume. There were also relationships with working memory, but none with measures of general cognitive or executive function. Follow-up analyses revealed several differential relationships with age between regional volume and sensorimotor performance. These relationships were predominantly selective to cerebellar regions that have been implicated in cognitive functions. Therefore, it may be the cognitive aspects of sensorimotor task performance that are best explained by individual differences in regional cerebellar volumes. In sum, our results demonstrate the importance of regional cerebellar volume with respect to both sensorimotor and cognitive performance, and we provide additional insight into the role of the cerebellum in age-related performance declines.     

Development of a Psychiatric Disorder Linked to Cerebellar Lesions

Cerebellar dysfunction plays a critical role in neurodevelopmental disorders with long-term behavioral and neuropsychiatric symptoms. A 43-year-old woman with a cerebellum arteriovenous malformation and history of behavioral dysregulation since childhood is described. After the rupture of the cerebellar malformation in adulthood, her behavior morphed into specific psychiatric symptoms and cognitive deficits occurred. The neuropsychological assessment evidenced impaired performance in attention, visuospatial, memory, and language domains. Moreover, psychiatric assessment indicated a borderline personality disorder. Brain MRI examination detected macroscopic abnormalities in the cerebellar posterior lobules VI, VIIa (Crus I), and IX, and in the posterior area of the vermis, regions usually involved in cognitive and emotional processing. The described patient suffered from cognitive and behavioral symptoms that are part of the cerebellar cognitive affective syndrome. This case supports the hypothesis of a cerebellar role in personality disorders emphasizing the importance of also examining the cerebellum in the presence of behavioral disturbances in children and adults.