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.     

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.     

The Cerebellum and Cognition: Evidence from Functional Imaging Studies

Evidence for a role of the human cerebellum in cognitive functions comes from anatomical, clinical and neuroimaging data. Functional neuroimaging reveals cerebellar activation during a variety of cognitive tasks, including language, visual?Cspatial, executive, and working memory processes. It is important to note that overt movement is not a prerequisite for cerebellar activation: the cerebellum is engaged during conditions which either control for motor output or do not involve motor responses. Resting-state functional connectivity data reveal that, in addition to networks underlying motor control, the cerebellum is part of ??cognitive?? networks with prefrontal and parietal association cortices. Consistent with these findings, regional differences in activation patterns within the cerebellum are evident depending on the task demands, suggesting that the cerebellum can be broadly divided into functional regions based on the patterns of anatomical connectivity between different regions of the cerebellum and sensorimotor and association areas of the cerebral cortex. However, the distinct contribution of the cerebellum to cognitive tasks is not clear. Here, the functional neuroimaging evidence for cerebellar involvement in cognitive functions is reviewed and related to hypotheses as to why the cerebellum is active during such tasks. Identifying the precise role of the cerebellum in cognition??as well as the mechanism by which the cerebellum modulates performance during a wide range of tasks??remains a challenge for future investigations.     

The neural basis of ataxic dysarthria

Lesions to the cerebellum often give rise to ataxic dysarthria which is characterized by a primary disruption to articulation and prosody. Converging evidence supports the likelihood of speech motor programming abnormalities in addition to speech execution deficits. The understanding of ataxic dysarthria has been further refined by the development of neural network models and neuroimaging studies. A critical role of feedforward processing by the cerebellum has been established and linked to speech motor control and to aspects of ataxic dysarthria. Moreover, this research has helped to define models of the cerebellar contributions to speech processing and production, and to posit possible regions of speech localization within the cerebellum. Bilateral, superior areas of the cerebellum appear to mediate speech motor control while a putative role of the right cerebellar hemispheres in the planning and processing of speech has been suggested.     

Neuropsychological deficits in cerebellar syndromes

Interest in the role of the cerebellum in cognitive functioning has been increasing in recent years, based on both theoretical considerations and empirical evidence. This review attempts to critically evaluate neuropsychological studies based on standardized testing of patients with selective cerebellar dysfunction. Findings are considered which address possible cerebellar influence on motor adaptation and habituation, motor skill acquisition, classical conditioning of motor responses, temporal processing, general intellectual abilities, frontal lobe functions, visuospatial abilities, memory and non-motor skill learning, and language. Deficits in motor learning and temporal processing are consistently observed in patients with cerebellar syndromes, while deficits in frontal lobe functions, visuospatial processing, memory, non-motor skill learning and language dysfunction have been reported in several studies, but have not been replicated in others. Methodological factors which may account for such discrepancies are discussed.     

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.     

The cognitive neuropsychology of the cerebellum

We review evidence from neuropsychological studies of patients with damage to the cerebellum that suggests cerebellar involvement in four general categories of cognition: (1) speech and language; (2) temporal processing; (3) implicit learning and memory; (4) visuospatial processing and attention. A relatively strong case can be made for cerebellar contributions to language (including speech perception, lexical retrieval, and working memory) and to temporal processing. However, the evidence concerning cerebellar involvement in non-motor implicit learning and visuospatial processing is more equivocal. We argue that cerebellar contributions to cognition are computationally plausible, given its reciprocal connectivity with the cerebral cortex, and suggest that this function of the cerebellum may be an example of an evolutionary process by which mechanisms originally evolved for one function (in this case, motor control) are adapted to other functions (cognition).     

Cognition in Friedreich Ataxia

Friedreich ataxia (FRDA) is the most frequent of the inherited ataxias. However, very few studies have examined the cognitive status of patients with genetically defined FRDA. Our aim was to study cognitive performance of FRDA patients taking into account the motor problems characteristic of this clinical population. Thirty-six FRDA patients were administered a comprehensive neuropsychological battery measuring multiple domains: processing speed, attention, working memory, executive functions, verbal and visual memory, visuoperceptive and visuospatial skills, visuoconstructive functions, and language. Thirty-one gender, age, years of education, and estimated IQ-matched healthy participants served as control subjects. All participants were native Spanish speakers. Patients showed decreased motor and mental speed, problems in conceptual thinking, a diminished verbal fluency, deficits in acquisition of verbal information and use of semantic strategies in retrieval, visuoperceptive and visuoconstructive problems, and poor action naming. Scores on the depression inventory were significantly higher in patients than controls, but depression did not account for group differences in cognitive performance. The observed pattern of neuropsychological impairment is indicative of executive problems and parieto-temporal dysfunction. Neuropathological and neuroimaging studies with FRDA patients have reported only mild anomalies in cerebral hemispheres. Thus, cognitive impairment in FRDA is probably caused by the interruption of the cerebro-cerebellar circuits that have been proposed as the anatomical substrate of the cerebellar involvement in cognition.     

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.     

The role of transcranial magnetic stimulation in the study of cerebellar cognitive function

Transcranial magnetic stimulation (TMS) allows non-invasive stimulation of brain structures. This technique can be used either for stimulating the motor cortex, recording motor evoked potentials from peripheral muscles, or for modulating the excitability of other non-motor areas in order to establish their necessity for a given task. TMS of the cerebellum can give interesting insights on the cerebellar functions. Paired-TMS techniques, delivering stimuli over the cerebellum followed at various interstimulus intervals by stimuli over the motor cortex, allow studying the pattern of connectivity between the cerebellum and the contralateral motor cortex in physiological as well as in pathological conditions. Repetitive TMS, delivering trains of stimuli at different frequencies, allows interfering with the function of cerebellar circuits during the execution of cognitive tasks. This application complements neuropsychological and neuroimaging studies in the study of the cerebellar involvement in a number of cognitive operations, ranging from procedural memory, working memory and learning through observation.     

The cerebellum and language: Historical perspective and review

Investigation of a possible role for the cerebellum in the mediation of cognitive processes, including language, has historically been overshadowed by research interest in cerebellar coordination of motor control. Over the past two decades, however, the question of a possible participation of the cerebellum in language processing itself has come to the forefront. In particular recent advances in our understanding of the neuroanatomy of the cerebellum combined with evidence from functional neuroimaging, neurophysiological and neuropsychological research, have extended our view of the cerebellum from that of a simple coordinator of autonomic and somatic motor function. Rather it is now more widely accepted that the cerebellum, and in particular the right cerebellar hemisphere, participates in modulation of cognitive functioning, especially to those parts of the brain to which it is reciprocally connected. The present paper reviews the neuroanatomical, clinical and functional neuroimaging evidence suggestive of a role for the cerebellum in language processing. The possible neuropathophysiological substrates of language impairment associated with cerebellar pathology are discussed and the nature of the linguistic deficits associated with disease or damage to the cerebellum described.     

Multiple system atrophy with early cognitive deficits: A case report

We present the case of a patient with multiple system atrophy with predominant cerebellar ataxia (MSA-C) in the early stage of the disease, who was assessed using a comprehensive neuropsychological test battery. Many studies have found cognitive deficits in MSA patients assessed after 2–3 years, but not in the first stages of the disease. The aim of this paper is to stress the importance of a complete neuropsychological assessment, even at the initial stage of the disease, when instrumental examinations are not able to show cortical involvement and daily life activities have not been affected. The neuropsychological tests examined general cognition, verbal and visual memory, visuospatial and constructional ability, language, executive function, depression and functional autonomy. Results showed cognitive deficits in executive functions, above all in the control and inhibition of automatic response, planning and reasoning abilities, memory and visuoconstructional functions. However, these problems did not affect the patient’s autonomy in everyday life. MRI scan showed the involvement of the cerebellum and the fibers of the pons and raphe, with normal cerebral ventricles and sulci. The cognitive deficits in our patient could be explained by a disruption in cerebrocerebellum connections between the frontal areas and the cerebellar structures. These results show that a more comprehensive cognitive evaluation is necessary to detect early the onset of neuropsychological deficits, also in order to begin in time adequate rehabilitation programs.     

Cognitive Impairment in ARCA-1, a Newly Discovered Pure Cerebellar Ataxia Syndrome

Cerebellar contribution to non-motor functions has been supported by several animal, human and functional neuroimaging studies. Which cognitive skills and to what extent the cerebrocerebellar loops contribute remain unclear, however. Among other reasons, this may be explained by the fact that authors have studied patients with extracerebellar lesions. The goal of this study was to explore the role of the cerebellum in cognition and affect in patients with autosomal recessive cerebellar ataxia type 1 (ARCA-1), a newly described inherited cerebellar disease characterised by middle-age onset of ataxia as well as pure, severe and diffuse cerebellar atrophy. To this end, the performance of 21 ARCA-1 patients was compared to that of 21 normal controls paired for age and education on a 3-h battery of attention, executive, visuospatial and memory skills. Results indicated similar IQ, naming and declarative memory abilities between groups. ARCA-1 patients showed significant deficits in attention (attention span, speed of information processing, sustained attention), verbal working memory and visuospatial/visuoconstructional skills (3-D drawings, copy of a complex figure). Functional brain imaging in a subset of patients showed diffuse severe cerebellar hypometabolism associated with a small area of right parietal hypometabolism. None of the patients presented a significant affective syndrome. Correlational analyses suggested that cognitive deficits could not be explained by the severity of motor deficits, duration of disease or mood. Altogether, this study confirms that pure cerebellar damage as seen in ARCA-1 is associated with significant cognitive impairments but not with psychiatric comorbidity. These deficits are correlated with an overall moderate impact on patient’s autonomy. Our data favour an indirect participation of the dorsolateral prefrontal and posterior parietal cortical areas to the cerebrocerebellar circuit.     

Contribution of the cerebellum to cognition

The role of the cerebellum in motor control and motor learning is well-recognised. Patients with cerebellar disease consult a doctor because of their motor dysfunction (ataxia). For nearly three decades intense research has been addressing the question to what extent the cerebellum may support cognitive functions. Neuroanatomic findings support the notion that posterolateral parts of the cerebellum contribute to cognition. Although there is a huge number of neuropsychological studies in patients with cerebellar disease, interpretation of findings is frequently hampered by the accompanying motor disorders and extracerebellar lesions. This review summarises the anatomic findings and attempts to give a critical evaluation of findings in human lesion studies. There are good reasons to believe that cerebellar disorders, both cerebellar degeneration and focal cerebellar lesions, may lead to certain cognitive dysfunctions. Disorders in executive function, in particular working memory, and certain higher language tasks are best documented. However, disorders in adults with chronic diseases tend to be mild. Dysfunction appears to be more prominent in patients with acute disease.     

A meta‐analysis of cerebellar contributions to higher cognition from PET and fMRI studies

A growing interest in cerebellar function and its involvement in higher cognition have prompted much research in recent years. Cerebellar presence in a wide range of cognitive functions examined within an increasing body of neuroimaging literature has been observed. We applied a meta‐analytic approach, which employed the activation likelihood estimate method, to consolidate results of cerebellar involvement accumulated in different cognitive tasks of interest and systematically identified similarities among the studies. The current analysis included 88 neuroimaging studies demonstrating cerebellar activations in higher cognitive domains involving emotion, executive function, language, music, timing and working memory. While largely consistent with a prior meta‐analysis by Stoodley and Schmahmann ( 2009 : Neuroimage 44:489‐501), our results extended their findings to include music and timing domains to provide further insights into cerebellar involvement and elucidate its role in higher cognition. In addition, we conducted inter‐ and intradomain comparisons for the cognitive domains of emotion, language, and working memory. We also considered task differences within the domain of verbal working memory by conducting a comparison of the Sternberg with the n‐back task, as well as an analysis of the differential components within the Sternberg task. Results showed a consistent cerebellar presence in the timing domain, providing evidence for a role in time keeping. Unique clusters identified within the domain further refine the topographic organization of the cerebellum. Hum Brain Mapp 35:593–615, 2014. © 2012 Wiley Periodicals, Inc.     

Cognitive and Emotional Deficits in Chronic Alcoholics: a Role for the Cerebellum?

It is now widely accepted that in addition to motor coordination, the cerebellum is also involved in the modulation of cognitive and affective processes. Despite alcoholic cerebellar degeneration (ACD) being the most common form of cerebellar disorder, little systematic investigation of cerebellar-mediated cognitive and affective deficits has occurred in chronic alcoholics. Forty-nine chronic alcoholics and 29 healthy control participants underwent testing of cognitive and affective function, along with measurement of cerebellar ataxia using the International Cooperative Ataxia Rating Scale (Trouillas et al., Journal of the Neurological Sciences 145:205–11, 1997). The alcoholic group demonstrated significantly poorer performance as compared to the control group in a number of domains, including visuospatial and language skills, psychomotor speed, new learning and memory, executive functioning, and emotional regulation and affect processing. There were no differences between the alcoholic and control groups in immediate attention and working memory abilities. Years of heavy drinking and total period of abstinence were found to be the best predictors of cognitive and emotional function in the alcoholic group. After accounting for alcohol chronicity, there was still a relationship between the degree of clinical signs of ACD and some areas of cognitive and emotional functioning, including language, executive functioning, processing speed and affect processing. The results suggest that some of the cognitive and affective deficits observed in chronic alcoholics may be mediated, at least in part, by cerebellar dysfunction. These findings add support to the theory of disruption to bidirectional cerebro-cerebellar circuitry underlying cognitive and affective deficits in chronic alcoholics.     

The role of the cerebellum in the pathophysiology and treatment of neuropsychiatric disorders: a review

The cerebellum has traditionally been looked upon as a brain area primarily involved in motor behaviour. The last decade has however heralded the cerebellum as a brain region of renewed interest for neuropsychiatric disorders. This renewed interest is fuelled by new insights obtained from neuroanatomical research, modern functional neuroimaging and transcranial magnetic stimulation studies. In this review, evidence in support of cerebellar involvement in neuropsychiatric disorders will be presented. In addition, transcranial magnetic stimulation will be introduced as a novel way to study cerebellar contributions to the pathophysiology of psychiatric disorders. In conclusion, a new functional concept of the cerebellum as more than simply a brain area regulating motor control appears mandatory and the involvement of the cerebellum should be considered when studying the neurological basis of neuropsychiatric disorders.     

Lack of normal association between cerebellar volume and neuropsychological functions in first-episode schizophrenia

OBJECTIVE: Functional neuroimaging studies have identified a role for the cerebellum in the neuropsychology of schizophrenia. Few studies, however, have examined the relationship between cerebellar size and neuropsychological functioning in schizophrenia. The authors' goal was to examine this relationship in patients and healthy comparison subjects. METHOD: Total cerebellar volume was computed from magnetic resonance images in 48 male and 33 female patients experiencing a first episode of schizophrenia and in 14 male and nine female healthy comparison subjects. Patients and comparison subjects completed a comprehensive neuropsychological assessment encompassing six domains of functioning: executive, motor, language, visuospatial, memory, and attention. A global domain of functioning was computed as the mean of these six domains. RESULTS: Larger cerebellar volume correlated significantly with better global functioning in healthy subjects but not among patients with schizophrenia; this relationship was significantly stronger in healthy subjects than in patients. Additional analyses revealed significant associations between cerebellar volume and visuospatial, executive, and memory functions in healthy volunteers but not among patients. CONCLUSIONS: The cerebellum plays a role in higher cognitive functions in healthy individuals, and normal associations between cerebellar size and function are absent in patients experiencing a first episode of schizophrenia. These findings are consistent with neurobiological models implicating the cerebellum in the pathogenesis of schizophrenia.     

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."