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.     

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.     

Functional activation in the cerebellum during working memory and simple speech tasks

Verbal working memory is the ability to temporarily store and manipulate verbal information. This study tested the predictions of a neuroanatomical model of how the cerebellum contributes to verbal working memory (Desmond et al., 1997). In this model, a large bilateral region in the superior cerebellum is associated with articulatory rehearsal and a right-lateralized region in the inferior cerebellum is associated with the correction of errors within the working memory system. The Desmond et al. (1997) model was based on neuroimaging findings using item recognition tasks and comparisons between working memory and covert rehearsal tasks, whereas in this functional magnetic resonance imaging (fMRI) study we used a delayed serial recall (DSR) task because it relies more heavily on articulatory rehearsal, and our comparison tasks included both overt and covert speech tasks. Our results provide some support for the Desmond et al. (1997) model. In particular, we found multiple activation foci within the superior and inferior sectors of the cerebellum and evidence that these regions show different patterns of activation across working memory and speech tasks. However, the specific patterns of activation were not fully consistent with those reported by Desmond et al. (1997). Namely, our results indicate that activation in the superior sector should be functionally subdivided into a medial focus involved in speech processing and a lateral focus more specific to verbal working memory; the results also indicate that activation in the inferior sector is not uniquely right lateralized. These complex findings speak to the need for future studies to consider the speech-motor aspects of tasks, to investigate the functional significance of adjacent peaks of activation within large regions of cerebellar activation, and to use analysis procedures that support regional distinctions through direct statistical tests. Such studies would help to refine our understanding of how the cerebellum contributes to speech and verbal working memory.     

Cerebellar involvement in cognitive function: evidence from neuroimaging

A variety of evidence derived from functional neuroimaging suggests that the cerebellum participates in cognitive function, a conclusion consistent with the results of studies of patients with cerebellar damage and with recent advances in the understanding of cortiocerebellar pathways. This review focuses on the importance of cerebro-cerebellar interactions in understanding cerebellar influences on neocortical function. First, the phenomenon of crossed-cerebellar diaschisis, and the converse occurrence of neocortical hypometabolism following cerebellar damage, is discussed in light of imaging studies demonstrating the coupling between these structures during specific cognitive tasks. Then, using the pattern of cerebellar activation in verbal working memory as a model, experiments are reviewed that demonstrate a specific topology of the functional connectivity of the cerebellum and the neocortex, leading to the hypothesis that the articulatory control system may be mediated by a frontal cortex-superior cerebellar loop, while phonological storage may be mediatated by a temporal/parietal-inferior cerebellar loop. Overall, the set of observations illustrate how neuroimaging can help bridge the gap between neuroanatomy and cognitive psychology.     

Temporal dynamics of cerebro-cerebellar network recruitment during a cognitive task

Previous investigations have demonstrated that two regions in the right cerebellum, one located superiorly in hemispheral lobule VI/Crus I and another located inferiorly in hemispheral lobule VIIB/VIIIA, are activated during verbal working memory performance. On the basis of functional neuroimaging patterns of activation, as well as known cortico-pontine and ponto-cerebellar projections, the superior region has been hypothesized to contribute to the articulatory control system of working memory whereas the inferior region has been linked to the phonological store. The present study used event-related fMRI and individual estimates of hemodynamic response for both the cerebellum and neocortex to test this model and characterize the task phase specific cerebro-cerebellar activations for a Sternberg verbal working memory task. Results demonstrated that the right superior cerebellum showed the strongest activation during the initial encoding phase of the task, and, consistent with predictions, a similar pattern was observed in left opercular inferior frontal and premotor regions. In contrast, the right inferior cerebellum exhibited the greatest activation during the maintenance phase of the task, and as predicted, corresponded with activation in the left inferior parietal lobule. The significance of the results with respect to cerebro-cerebellar models of verbal working memory and to theoretical accounts of cerebellar involvement in cognition is discussed.     

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.     

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 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.     

Cerebellum: Connections and Functions

In addition to its role in motor control, reflex adaptation, and motor learning, three sorts of evidence have been put forward to support the idea that the cerebellum may also be involved in cognition. Patients with cerebellar lesions are reported to have deficits in performing one or another cognitive task. The cerebellum is often seen to be activated when normal subjects perform such tasks. There are connections to and from areas of the prefrontal cortex that may be involved in cognition. In this paper, we review the anatomical evidence to support the claim. We suggest that there are only minor connections with cognitive areas of the cerebral cortex and that some of the imaging evidence may reflect the cerebellum’s role in the control of eye movements rather than cognition.     

Distinct critical cerebellar subregions for components of verbal working memory

A role for the cerebellum in cognition has been proposed based on studies suggesting a profile of cognitive deficits due to cerebellar stroke. Such studies are limited in the determination of the detailed organisation of cerebellar subregions that are critical for different aspects of cognition. In this study we examined the correlation between cognitive performance and cerebellar integrity in a specific degeneration of the cerebellar cortex: Spinocerebellar Ataxia type 6 (SCA6). The results demonstrate a critical relationship between verbal working memory and grey matter density in superior (bilateral lobules VI and crus I of lobule VII) and inferior (bilateral lobules VIIIa and VIIIb, and right lobule IX) parts of the cerebellum. We demonstrate that distinct cerebellar regions subserve different components of the prevalent psychological model for verbal working memory based on a phonological loop. The work confirms the involvement of the cerebellum in verbal working memory and defines specific subsystems for this within the cerebellum.     

The attentive cerebellum — myth or reality?

Based on the discovery of significant cerebellar projections into associative cortices and the observation of cerebellar abnormalities in autistic children, the concept has been put forward that the cerebellum might contribute to cognitive functions including attention. Specifically, a deficit analogous to motor dysmetria has been envisaged as a consequence of cerebellar damage-the ‘dysmetria of attention’. This paper provides a review of patient studies and imaging studies which have been performed so far in order to test this concept. Although several sudies report on attention deficits of patients with cerebellar damage, a closer look at the specific paradigms used reveals that disturbances have only been observed consistently for tasks involving significant oculomotor, motor, and/or working memory demands. Likewise, cerebellar activations in imaging studies on attention seem to reflect oculomotor or other motor behavior rather than true involvement in attention. Both attempts have failed so far to consistently reveal cerebellar involvement in attention when confounding influences were controlled. We, therefore, conclude that the concept of attentional dysmetria as a consequence of cerebellar damage is not adequately supported.     

The cerebellum in cognitive processes: Supporting studies in children

Over the last decade, increasing evidence of cognitive functions of the cerebellum during development and learning processes could be ascertained. Posterior fossa malformations such as cerebellar hypoplasia or Joubert syndrome are known to be related to developmental problems in a marked to moderate extent. More detailed analyses reveal special deficits in attention, processing speed, visuospatial functions and language. A study about Dandy Walker syndrome states a relationship of abnormalities in vermis lobulation with developmental problems. Further lobulation or volume abnormalities of the cerebellum and/or vermis can be detected in disorders as fragile X syndrome, Downs’s syndrome or William’s syndrome. Neuropsychological studies reveal a relation of dyslexia and attention deficit disorder with cerebellar functions. These functional studies are supported by structural abnormalities in neuroimaging in these disorders. Acquired cerebellar or vermis atrophy was found in groups of children with developmental problems such as prenatal alcohol exposure or extreme prematurity. Also focal lesions during childhood or adolescence such as cerebellar tumour or stroke are related with neuropsychological abnormalities, which are most pronounced in visuo-spatial, language and memory functions. In addition, cerebellar atrophy was shown to be a bad prognostic factor considering cognitive outcome in children after brain trauma and leukaemia. In ataxia teleangiectasia, a neurodegenerative disorder affecting primarily the cerebellar cortex, a reduced verbal IQ and problems of judgment of duration are a hint of the importance of the cerebellum in cognition. In conclusion, the cerebellum seems to play an important role in many higher cognitive functions especially in learning. There is a suggestion that the earlier the incorrect influence the more pronounced the problems.     

Cerebellar Disorders in Childhood: Cognitive Problems

Over the last decade, increasing evidence of cognitive functions of the cerebellum during development and learning processes could be ascertained. Posterior fossa malformations such as cerebellar hypoplasia or Joubert syndrome are known to be related to developmental problems in a marked to moderate extent. More detailed analyses reveal special deficits in attention, processing speed, visuospatial functions, and language. A study about Dandy Walker syndrome states a relationship of abnormalities in vermis lobulation with developmental problems. Further lobulation or volume abnormalities of the cerebellum and/or vermis can be detected in disorders as fragile X syndrome, Downs’s syndrome, William’s syndrome, and autism. Neuropsychological studies reveal a relation of dyslexia and attention deficit disorder with cerebellar functions. These functional studies are supported by structural abnormalities in neuroimaging in these disorders. Acquired cerebellar or vermis atrophy was found in groups of children with developmental problems such as prenatal alcohol exposure or extreme prematurity. Also, focal lesions during childhood or adolescence such as cerebellar tumor or stroke are related with neuropsychological abnormalities, which are most pronounced in visuospatial, language, and memory functions. In addition, cerebellar atrophy was shown to be a bad prognostic factor considering cognitive outcome in children after brain trauma and leukemia. In ataxia teleangiectasia, a neurodegenerative disorder affecting primarily the cerebellar cortex, a reduced verbal intelligence quotient and problems of judgment of duration are a hint of the importance of the cerebellum in cognition. In conclusion, the cerebellum seems to play an important role in many higher cognitive functions, especially in learning. There is a suggestion that the earlier the incorrect influence, the more pronounced the problems.     

Pathological amygdala activation during working memory performance: Evidence for a pathophysiological trait marker in bipolar affective disorder

Recent evidence suggests that deficits of working memory may be a promising neurocognitive endophenotype of bipolar affective disorder. However, little is known about the neurobiological correlates of these deficits. The aim of this study was to determine possible pathophysiological trait markers of bipolar disorder in neural circuits involved in working memory. Functional magnetic resonance imaging was performed in 18 euthymic bipolar patients and 18 matched healthy volunteers using two circuit‐specific experimental tasks established by prior systematic neuroimaging studies of working memory. Both euthymic bipolar patients and healthy controls showed working memory‐related brain activations that were highly consistent with findings from previous comparable neuroimaging studies in healthy subjects. While these patterns of brain activation were completely preserved in the bipolar patients, only the patients exhibited activation of the right amygdala during the articulatory rehearsal task. In the same task, functional activation in right frontal and intraparietal cortex and in the right cerebellum was significantly enhanced in the patients. These findings indicate that the right amygdala is pathologically activated in euthymic bipolar patients during performance of a circuit‐specific working memory task (articulatory rehearsal). This pathophysiological abnormality appears to be a trait marker in bipolar disorders that can be observed even in the euthymic state and that seems to be largely independent of task performance and medication. Hum Brain Mapp, 2010. © 2009 Wiley‐Liss, Inc.     

Dynamic interactions between neural systems underlying different components of verbal working memory

Summary Brain functions are determined not only by processing in single brain areas but also by dynamic interactions within and between distributed neural networks. We investigated functional connectivity between two brain systems underlying complementary components of verbal working memory. The use of the articulatory rehearsal (“inner speech”) mechanism enhanced neural activity in ventral premotor cortex and Broca’s area. These activations showed a negative functional coupling with anatomically connected brain regions subserving the non-articulatory maintenance of phonological information, i.e. the “inner ear”.     

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.     

Consensus Paper: Language and the Cerebellum: an Ongoing Enigma

In less than three decades, the concept “cerebellar neurocognition” has evolved from a mere afterthought to an entirely new and multifaceted area of neuroscientific research. A close interplay between three main strands of contemporary neuroscience induced a substantial modification of the traditional view of the cerebellum as a mere coordinator of autonomic and somatic motor functions. Indeed, the wealth of current evidence derived from detailed neuroanatomical investigations, functional neuroimaging studies with healthy subjects and patients and in-depth neuropsychological assessment of patients with cerebellar disorders shows that the cerebellum has a cardinal role to play in affective regulation, cognitive processing, and linguistic function. Although considerable progress has been made in models of cerebellar function, controversy remains regarding the exact role of the “linguistic cerebellum” in a broad variety of nonmotor language processes. This consensus paper brings together a range of different viewpoints and opinions regarding the contribution of the cerebellum to language function. Recent developments and insights in the nonmotor modulatory role of the cerebellum in language and some related disorders will be discussed. The role of the cerebellum in speech and language perception, in motor speech planning including apraxia of speech, in verbal working memory, in phonological and semantic verbal fluency, in syntax processing, in the dynamics of language production, in reading and in writing will be addressed. In addition, the functional topography of the linguistic cerebellum and the contribution of the deep nuclei to linguistic function will be briefly discussed. As such, a framework for debate and discussion will be offered in this consensus paper.     

Diagnosis-specific effect of familial loading on verbal working memory in schizophrenia

Background  Working memory disturbances are a frequently replicated finding in schizophrenia and less consistent also in schizoaffective disorder. Working memory dysfunctions have been shown to be heritable and have been proposed to represent a promising endophenotype of schizophrenic psychoses. Methods   In the present study, we investigated the effects of familial loading on performance rates in circuit-specific verbal and visuospatial working memory tasks in matched samples of schizophrenic patients (from multiply affected or uniaffected families), schizoaffective patients (from multiply affected or uniaffected families), and healthy subjects. Results  We found a significant interaction effect between familial loading and diagnosis in terms of a diagnosis-specific detrimental effect of familial loading on the performance of schizophrenic (but not schizoaffective) patients in the articulatory rehearsal task. Conclusion  This finding of a circuit-specific verbal working memory deficit in schizophrenic patients with additional familial loading is consistent with prior studies, which provided evidence for the existence of specific subgroups of schizophrenic patients with selective working memory impairments and for diagnosis-specific dysfunctions of the articulatory rehearsal mechanism in schizophrenic, but not in schizoaffective patients. Together, these findings suggest that the genetic risk for (a subtype of) schizophrenia may be associated with dysfunctions of the brain system, which underlies the articulatory rehearsal mechanism, the probably phylogenetically youngest part of human working memory.     

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).     

Cerebellar Contributions to Verbal Working Memory

There is increasing evidence for a cerebellar role in working memory. Clinical research has shown that working memory impairments after cerebellar damage and neuroimaging studies have revealed task-specific activation in the cerebellum during working memory processing. A lateralisation of cerebellar function within working memory has been proposed with the right hemisphere making the greater contribution to verbal processing and the left hemisphere for visuospatial tasks. We used continuous theta burst stimulation (cTBS) to examine whether differences in post-stimulation performance could be observed based on the cerebellar hemisphere stimulated and the type of data presented. We observed that participants were significantly less accurate on a verbal version of a Sternberg task after stimulation to the right cerebellar hemisphere when compared to left hemisphere stimulation. Performance on a visual Sternberg task was unaffected by stimulation of either hemisphere. We discuss our results in the context of prior studies that have used cerebellar stimulation to investigate working memory and highlight the cerebellar role in phonological encoding.