Cerebellar neurocognition: Insights into the bottom of the brain

Clinical Neurology and Neurosurgery 110 (2008) 763–773

Review

Cerebellar neurocognition: Insights into the bottom of the brain Hanne Baillieux a , Hyo Jung De Smet a , Philippe F. Paquier a,b,c , Peter P. De Deyn d,e , Peter Mari¨en a,d,e,∗ a Department of Linguistics, Vrije Universiteit Brussel, Brussels, Belgium Department of Neurology, Hˆopital Universitaire Erasme ULB, Brussels, Belgium c Unit of Neurosciences, Universiteit Antwerpen, Antwerp, Belgium d Department of Neurology, ZNA Middelheim, Antwerp, Belgium Laboratory of Neurochemistry and Behaviour, Institute Born-Bunge, Universiteit Antwerpen, Antwerp, Belgium b

e

Received 25 February 2008; received in revised form 24 April 2008; accepted 13 May 2008

Abstract 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. © 2008 Elsevier B.V. All rights reserved. Keywords: Review; Cerebellum; Cognition; Behavior; Affective regulation

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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The cerebellum and cognition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Executive functioning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Learning and memory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.1. Learning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.2. Memory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Attention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. Visuo-spatial regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5. Language . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The cerebellum and behavioral-affective regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acquired syndromes following cerebellar lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Corresponding author at: ZNA AZ Middelheim, Lindendreef 1, B-2020 Antwerp, Belgium. Tel.: +32 3 280 31 36; fax: +32 3 281 37 48. E-mail addresses: [email protected], [email protected] (P. Mari¨en).

0303-8467/$ – see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.clineuro.2008.05.013

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H. Baillieux et al. / Clinical Neurology and Neurosurgery 110 (2008) 763–773

4.1. The cerebellar cognitive affective syndrome (CCAS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. The posterior fossa syndrome (PFS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction At the beginning of the 20th century, Joseph Babinski first described the inability of patients with cerebellar lesions to perform rapid successive alternating movements and defined this phenomenon “dysdiadochokinesia” [1]. During the same period, the Italian physiologist Luigi Luciani described a triad of symptoms, including lack of muscle tone, lack of strength, and incoordination due to cerebellar disease, which was later named the “Luciani syndrome” [2]. Two decades later, Gordon Holmes published his famous “Croonian Lectures” in which he reported abnormal speech characterized by an indistinct articulation in patients with cerebellar lesions [3]. As a result, coordination, balance and motor speech regulation were defined as the core functions of the cerebellum. This common belief on cerebellar functioning lasted throughout the 20th century. However, neuroanatomical, neuroimaging and clinical studies recently provided evidence of cerebellar involvement in cognitive and linguistic functioning. Neuroanatomical studies disclosed bidirectional pathways connecting the cerebellum to important parts of the cerebral cortex involved in cognitive regulation [4,5]. In the early 1990s, Middleton and Strick [6] discovered that the deep cerebellar nuclei send information to prefrontal areas through dentatothalamic pathways, while the prefrontal cortex sends information back to the cerebellum via pontine nuclei. In addition, the development of more sensitive neuropsychological tests and the growing awareness of the importance of standardized neuropsychological bed-side screening instruments resulted in a significant attentiveness towards possible cognitive and linguistic dysfunctions in patients with cerebellar lesions. This resulted in a variety of single case reports [5,7–9], in which cognitive and linguistic symptoms were described in association with isolated cerebellar lesions. In this review, the contribution of the cerebellum to various cognitive functions will be discussed. Clinical studies of adult patients with cerebellar lesions as well as results of functional neuroimaging studies will be presented and related to current knowledge on cerebellar functioning. In addition, the cerebellar role in behavioral-affective regulation will be discussed.

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titasking, problem-solving and inhibition, necessary to plan and direct goal-oriented behavior. It is generally accepted that the prefrontal cortex (PFC) is crucially involved in the maintenance of executive control. Neuroanatomical studies have shown strong fronto-cerebellar connectivity, consisting of closed cortico-cerebellar loops in which the (dorso)lateral part of the prefrontal cortex connects to the cerebellum via pontine nuclei while the cerebellum sends projections back to the PFC via the dentate nucleus and thalamus [11,12] (Fig. 1, with permission adapted from Schmahmann [11] and Heyder et al. [12]). Cerebellar involvement in executive functioning has been documented by both functional neuroimaging studies in healthy subjects and by clinical studies of patients with cerebellar lesions. Recently, Lie et al. [13] identified cerebellar activations via fMRI in healthy subjects during performance on the Wisconsin Card Sorting Test (WCST), a test widely applied to assess executive abilities. In addition, a PET study by Ravnkilde et al. [14] found cerebellar activation during the execution of the interference part (card III) of the Stroop Color Word Test, an instrument generally used to assess frontal attention and inhibition processes. Other studies found cerebellar activation during problem-solving, planning tasks and multitasking, such as the “Tower of London” test [15], verbal fluency tasks [16] and dual tasks compared to single task conditions [17]. In addition, clinical studies of patients with isolated cerebellar lesions have demonstrated a broad spectrum of executive disturbances. In a recent study by Kalashnikova et al. [18], 25 patients with cerebellar infarcts were investigated by means of an extensive neuropsychological test battery. Symptoms indicating dysfunction of the prefrontal areas were detected in 22 patients. These patients had diffi-

2. The cerebellum and cognition 2.1. Executive functioning The term “executive functions” refers to the ability to coordinate different cognitive tasks to obtain a certain goal [10]. It consists of a variety of cognitive abilities, such as mul-

Fig. 1. Connections between the cerebellum and the neocortex (after Schmahmann [11]).

H. Baillieux et al. / Clinical Neurology and Neurosurgery 110 (2008) 763–773

culties in planning, problem-solving and mental flexibility. Following Schmahmann [19], the authors coined the difficulties “dysmetria of thought”, referring to an impairment of the coordinating role of the cerebellum. Furthermore, task management and multitasking are also considered as an explicit subcomponent of executive control. A study by Lang et al. [20] showed that patients with isolated cerebellar lesions obtained defective results during simultaneous performance of a movement and auditory task. Gottwald et al. [21] observed deficits in patients with focal cerebellar lesions who performed a divided attention task involving simultaneous processing of visual and auditory stimuli. Various studies exist in which executive disorders are documented after isolated cerebellar lesions [21,22–25]. Lalonde and BotezMarquard [26] described multiple difficulties on a variety of frontal tasks, such as mental flexibility, problem-solving and planning in adults with chronic cerebellar syndromes such as olivo-ponto-cerebellar atrophy and Friedreich ataxia. However, many issues regarding the functional implications of the fronto-cerebellar connectivity still remain unsolved. Functional neuroimaging and neurocognitive studies of cerebellar patients have not yielded univocal results [27]. For example, defective performances of patients with focal cerebellar lesions on the WCST or divided attention tasks have not been consistently found [12,28,29]. 2.2. Learning and memory 2.2.1. Learning Exploring the cerebellar role in learning and automatization of motor sequences already started several decades ago. Experimental studies in the early 1970s with cerebellar ablation in animals revealed impaired learning of motor sequences [30]. In addition, studies of patients with cerebellar lesions, focusing on vestibulo-ocular reflex adaptation [31], eye-blink conditioning [32,33] and learning of hand/arm movements [34] revealed cerebellar involvement in the process of motor learning. Recent research has extended this view with evidence for a role of the cerebellum in non-motor learning tasks. Fiez et al. [7], for example, described a patient who had impaired learning in implicit non-motor learning tasks, consisting of practice-related learning tasks. The role of the cerebellum in implicit learning was also supported by the observation that cerebellar patients showed impaired acquisition of eye-blink conditioning [35,36]. Patients with cerebellar lesions also consistently fail to accomplish learning on serial reaction time tasks [37], which are tasks in which the participants’ responses are based on the spatial position of series of stimuli that either follow a sequence or occur randomly. Healthy individuals generally respond faster to stimuli presented in a consistent sequence [38]. In addition, Quintero-Gallego et al. [39] studied the performance of children with posterior fossa tumor resections on declarative and procedural learning tasks and compared their performances to a matched control group. Results revealed significantly impaired procedural learning, while declarative

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learning was preserved [39]. Furthermore, Neau et al. [23] identified impairment in the learning condition of Rey’s word list in five patients with isolated cerebellar infarcts in the posterior inferior cerebellar artery territory (PICA). Finally, in a study of Drepper et al. [40], the performance on a cognitive associative learning task of nine patients with isolated degenerative cerebellar disorders was compared to a matched control group. Subjects were asked to learn an association between six pairs of colors and numerals by trial and error. Results clearly indicated that, in comparison to control subjects, cerebellar patients took significantly longer to learn the correct cognitive associations, suggesting a contribution of the cerebellum to cognitive associative learning [40]. 2.2.2. Memory In the early 1990s Appollonio et al. [41] studied 11 patients with cerebellar degenerative diseases and observed difficulties in explicit memory, while implicit and automatic memory remained intact. In a recent study by Gottwald et al. [21] memory functions in a group of 21 patients with acquired cerebellar lesions were investigated by means of the Wechsler Memory Scale-Revised [42]. Results showed marked difficulties in “free-recall” memory subtests (“logical memory” and “visual reproduction” subtests of the WMS-R). According to the authors, these memory subtests with a free recall condition demand more strategy and planning skills than structured memory tasks. As a result, the memory deficits were interpreted as secondary to deficits in executive functions. Another component of the memory system that has been the focus of much research is working memory (WM). A multi-component model of WM was proposed by Baddeley [43], comprising several subsystems usually referred to as the phonological loop (short-term storage of verbal material), the visuo-spatial sketchpad (short-term storage of visual material) and the central executive, constituting the general control-system. Inspired by Baddeley’s model, neuroimaging studies in the early 1990s began to investigate the neuronal substrate of WM. A study by Paulesu et al. [44] reported bilateral cerebellar activations and simultaneous activations in associative and sensorimotor cortical regions in healthy volunteers during verbal WM tasks. To date, several neuroimaging studies have confirmed cerebellar involvement in verbal WM tasks [45,46]. These findings are in accordance with several clinical studies. Recently, Ravizza et al. [47], for instance, investigated the cerebellar contribution to both visual and verbal WM tasks in 15 patients with isolated cerebellar lesions of vascular or neoplastic origin. Study results indicated that the performance on forward and backward verbal spans were significantly lower in cerebellar patients than in control subjects. Furthermore, the cerebellar patients tended to be more impaired on the verbal than on the spatial span tasks, which implies a cerebellar contribution to the phonological loop. Analyses of their results showed that the cerebellum plays an important role in the rehearsal system of the phonological loop responsible for the re-circulation

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of stored verbal information to prevent rapid decay. Furthermore, Ravizza et al. [47] suggested that a delay before recall is especially detrimental in patients with cerebellar damage and concluded that the cerebellum may contribute to verbal WM during the initial phonological encoding process. Results regarding cerebellar involvement in visuo-spatial WM tasks are less consistent [27]. Gottwald et al. [21] reported normal results on forward and backward visual memory spans in patients with isolated cerebellar lesions. In addition, a PET study by Jonides et al. [48] did not disclose cerebellar activation during spatial working memory tasks. A meta-analysis of functional neuroimaging studies on working memory [49] disclosed that cerebellar activity during spatial WM tasks is very rare, while consistent cerebellar activations are found during verbal WM tasks. Summing-up, it seems that the contribution of the cerebellum to working memory is domainspecific and only involves the verbal component of the WM system [50]. 2.3. Attention In the 1990s, studies of adult patients with acquired cerebellar lesions [51,52] provided preliminary evidence for a role of the cerebellum in various aspects of selective attention, such as orienting, distributing and shifting attention. More recently, Gottwald et al. [53] also investigated the hypothesis that the cerebellum contributes to specific aspects of attention. Sixteen patients with acquired focal cerebellar lesions were investigated in three different attention tasks, including selective attention, divided attention and working memory (which is, according to the authors very difficult to separate from attention). Results showed significant defects in the divided attention and working memory task but not in the selective attention task [53]. Moreover, their results showed that patients with right-sided cerebellar lesions were more impaired in attentional processes than patients with left-sided cerebellar lesions. This is a surprising finding given the fact that: (1) attentional processes are usually subserved by the right cerebral hemisphere [54,55] and (2) the cerebellar hemispheres project to the contralateral supratentorial regions by crossed cerebello-cerebral anatomical connections. However, the authors suggested that the observed attentional deficits can be explained by disruption of the right cerebellar connections to the left frontal regions, in which inhibition processes, as part of the executive system are located. This view implies that the attentional deficits in cerebellar patients are secondary to executive dysfunctions. However, results are not univocal. Exner et al. [56], for instance, found normal performance of cerebellar patients with isolated vascular lesions on focus attention tasks. In addition, both Golla et al. [57] and Hokkanen et al. [25] reported normal attentional shifting in patients with isolated cerebellar lesions. Functional neuroimaging data on the cerebellar role in attentional processes are also inconsistent. Allen et al. [58] first identified cerebellar activation during attentional processes independent of motor involvement. By means of fMRI,

it was demonstrated that attention and motor performance independently activate distinct cerebellar regions. Fig. 2 shows the most common sites of activation within the cerebellum during an attention task (A and B) and a motor task (C and D) (adapted from Allen et al. [58] with permission). In addition, paradigms assessing visuo-spatial attentional shifts also recorded cerebellar activations in the lateral cerebellar hemispheres and the posterior vermis [59,60]. However, as shown by Haarmeier and Their [61], these studies did not consider eye movements during scanning, leaving the question open that the cerebellar activation patterns could be the result of oculomotor movements. 2.4. Visuo-spatial regulation In 1994, Botez-Marquard et al. [8] described for the first time a patient with a left superior cerebellar artery (SCA) infarct and visuo-spatial disturbances, indicating focal dysfunction of the posterior right hemisphere. This observation was supported by SPECT data, showing a hypoperfusion in the basal ganglia and the frontoparietal areas of the right cerebral hemisphere. In 2001, Silveri et al. [62] described a patient with right-sided hemi-neglect and executive dysfunctions following an isolated right cerebellar lesion. Functional neuroimaging findings by means of SPECT disclosed a right cerebellar and bilateral frontal hypoperfusion, more pronounced in the left frontal lobe. The authors held crossed cerebello-cerebral diaschisis responsible for the clinical symptoms. Similar observations were made by Kalashnikova et al. [18] and Hokkanen et al. [25] who showed that patients with right-sided cerebellar lesions were generally more impaired in verbal functions, while patients with leftsided cerebellar lesions had more difficulty in visuo-spatial tasks. The cerebellar involvement in visuo-spatial abilities was more extensively investigated in 39 patients with focal or atrophic cerebellar damage by Molinari et al. [63]. Their results demonstrated that patients with both left and right cerebellar lesions presented with visuo-spatial symptoms. A comparison between visuo-spatial performance of subjects with right- versus left-sided cerebellar lesions showed significant differences in the characteristics of the visuo-spatial syndrome. Patients with right-sided cerebellar lesions were generally faster during the visuo-spatial task than the patients with left-sided lesion, but made more errors. According to the authors, a possible functional substrate of cerebellar induced visuo-spatial disorders lies in the ability to rotate objects mentally [63]. This conclusion was based on the observation that cerebellar patients performed normally on the subtest “block design” of the WAIS-III, a test in which the solution lies in direct manipulation of the parts, in comparison to the deficient performance of cerebellar patients on the Minnesota test [64], which can only be solved by mentally rotating the stimuli. It seems that cerebellar damage may affect the ability to perform visuo-spatial manipulations mentally. These clinical observations are in concordance with functional neuroimaging data showing cerebellar involvement in

H. Baillieux et al. / Clinical Neurology and Neurosurgery 110 (2008) 763–773

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Fig. 2. Functional maps demonstrating the most common sites of activation across subjects overlaid on an averaged coronal anatomical image of the cerebellum. During the attention task (A and B), the most common site of activation was in the left superior posterior cerebellum: the posterior portion of the quadrangular lobule (QuP) and the superior portion of the semilunar lobule (SeS). During the motor task (C and D), the most common site of activation was in the right anterior cerebellum: the anterior portion of the quadrangular lobule (QuA), the central lobule (C), and the anterior vermis (AVe). (With permission adapted from Allen et al. [58]).

a variety of visuo-spatial tasks. An fMRI study by Fink et al. [65], for instance, showed right parietal and left cerebellar activation during a line-bisection task in healthy subjects, while Lee et al. [66] reported bilateral cerebellar involvement by means of fMRI in a spatial orientation task. Other studies showing bilateral cerebellar activation during cognitive spatial tasks included mental rotation tasks [67] and visuo-motor imagery [68]. 2.5. Language Preliminary evidence in support of the view of a cerebellar involvement in linguistic functions was provided by PET activation studies which demonstrated that, in addition to Broca’s area, the contralateral right cerebellar hemisphere was active during verb generation tasks, which involved the visual presentation of a series of nouns for which the subject was asked to find a semantically related verb [69,70]. Data analysis showed that cerebellar activation was not related to the motor verbal response but to cognitive word association, proving cerebellar involvement in verbal fluency and word generation processes. Generally, the capacity to generate words according to a given rule is considered to depend on a close cooperation between verbal and executive abilities. It is clinically widely accepted that verbal fluency tasks explore frontal lobe functioning [71]. Despite variations on the original task design, various studies have consistently reported activation of the inferior lateral part of the right cerebellar hemisphere during word generation tasks [72–75]. Furthermore, the involvement of the cerebellum in word production was also reported by Fiez et al. [7] in a patient with a right cerebellar stroke. The authors for the first time used a specially designed retrieval task to evaluate their patient’s linguistic functions and observed semantic retrieval deficits, despite intact high-level conversational skills. Simi-

lar case reports of patients with verbal fluency problems were described by Silveri et al. [76], Botez-Marquard et al. [8], Paulus et al. [79] and Baillieux et al. [77]. Furthermore, word-finding difficulties have been frequently reported in patients with isolated cerebellar lesions [22,24,78,79]. In addition, a functional neuroimaging study by means of PET in 10 right-handed subjects [80] revealed cerebellar activation during a naming task of newly learned objects. The authors concluded that the naming of newly learned objects recruits more diffusely spread brain areas than the naming of familiar items, namely a network that includes fronto-temporal areas of the language dominant hemisphere and the cerebellum. Silveri et al. [76] were the first to report a patient with expressive agrammatism after isolated right cerebellar damage. Functional neuroimaging data by means of SPECT showed a relative hypoperfusion in the entire left cerebral hemisphere, which was more pronounced in the left posterior temporal region. The authors described their patient’s agrammatism as a “peripheral” disorder, following a general deficit in the timing functions of the cerebellum. More specifically, the cerebellar lesion was thought to cause a general delay in the processes underlying sentence construction. However, since then, expressive but also receptive agrammatism have been observed in patients with cerebellar lesions often associated with more extensive linguistic impairments [9,24,81–83]. The concept of cerebellar-induced aphasia, denoting a constellation of linguistic deficits in cerebellar patients, was introduced by Mari¨en et al. [9,82]. They reported long-term follow-up findings in a 73-year-old right-handed man with a right cerebellar ischemic lesion, who developed linguistic symptoms consistent with an aphasic disorder following prefrontal damage of the language dominant hemisphere. The language disorder was characterized by non-fluent aphasia,

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consisting of reduced speech initiation, decreased dynamics of language, word-finding disturbances, marked agrammatism and reading and writing difficulties. A SPECT study revealed crossed cerebello-cerebral diaschisis affecting the right cerebellar hemisphere and the left fronto-parietal region [9]. The observation that many reported patients developed linguistic deficits after focal right cerebellar lesions led to the notion of a lateralized linguistic cerebellum, emphasizing involvement of the right cerebellar hemisphere in linguistic processing, through crossed cerebello-cerebral connectivity [84]. Finally, additional studies have consistently demonstrated an involvement of the cerebellum in a variety of high-level language skills, such as language dynamics [84], metalinguistic abilities [78] and language proficiency [85].

3. The cerebellum and behavioral-affective regulation Nineteenth century reports anecdotally described aberrant behavior in patients with cerebellar lesions [86,87]. However, due to lack of standardized investigations and pathological verification, these observations did not receive much attention [88]. Renewed interest in the cerebellar involvement in behavioral and affective regulation arose after the introduction of the “cerebellar cognitive–affective syndrome” by Schmahmann and Sherman [29]. In their longitudinal followup study of 20 patients with cerebellar lesions, the authors observed prominent behavioral and affective changes, in some cases more overwhelming than the cognitive deficits. In total, 15 out of 20 patients presented with behavioral abnormalities and/or personality changes, which were described as flattening of affect or disinhibition characterized by overfamiliarity, flamboyant and impulsive actions or inappropriate comments. In some cases, behavior was regressive and child-like [29,19]. According to the authors, behavioral and affective symptoms were most notable when the lesion involved the vermis and paravermian region. Following the findings by Schmahmann and Sherman [29], a large spectrum of emotional and behavioral deficits have been described in patients with both acquired and congenital cerebellar damage, such as apathy and indifference [77], obsessive–compulsive traits [89], psychosis [90], dysphoria [79], aggressive behavior [91] and panic disorders [89]. From an anatomical point of view, various studies have shown bidirectional pathways linking the cerebellum to regions involved in emotional regulation [92,93]. The cerebellum is strongly connected with the reticular system (arousal), cortical association areas (cognitive processing of emotions) and limbic structures (emotional experience and expression), such as the amygdala, the hippocampus and the septal nuclei [93]. Finally, the notion that the cerebellum is involved in a variety of psychiatric diseases, such as schizophrenia, autism, depression and obsessive–compulsive disorder has been substantiated by evidence from morphological, metabolic and functional neuroimaging studies [89].

Reduced volume of the cerebellar vermis and cerebellar atrophy has been consistently found in schizophrenia [94] and depression [95]. However, more research is necessary to reveal the fundamental mechanisms by which the cerebellum modulates behavioral and affective regulation.

4. Acquired syndromes following cerebellar lesions 4.1. The cerebellar cognitive affective syndrome (CCAS) To address the issue whether cerebellar lesions are associated with uniform and clinically significant disturbances of cognition and behavior, Schmahmann and Sherman [29] conducted a 7 years follow-up study of 20 cerebellar patients by means of bed-side screenings and neuropsychological testing. Their results led to the introduction of the concept of “cerebellar cognitive affective syndrome” (CCAS), describing a coherent spectrum of cognitive and behavioral disturbances in adults following cerebellar damage. The syndrome consists of (1) executive dysfunctions such as disturbances in planning, set-shifting, abstract reasoning and working memory, (2) visuo-spatial deficits, such as impaired visuo-spatial organization and memory, (3) mild language symptoms including agrammatism and anomia and finally (4) behavioral-affective disturbances, consisting of blunting of affect or disinhibited and inappropriate behavior. In addition, arousal and alertness are not depressed, while specific “cortical” symptoms, such as aphasia, apraxia and agnosia were reported absent. Anatomoclinical analysis revealed that lesions of the posterior lobe of the cerebellum (PICA territory) were particularly important in the development of cognitive symptoms, while the vermis was consistently involved in patients with behavioral-affective disturbances. Exner et al. [56] recently investigated the hypothesis whether vascular lesions in different parts of the cerebellum result in differential cognitive and affective impairments. The authors concluded that a pattern of memory impairment, executive disturbances and emotional withdrawal can be found in patients with infarcts in the PICA territory, in contrast to subjects with SCA lesions. On the other hand, Neau et al. [23] found no significant differences between the cognitive consequences of infarcts in the PICA or the SCA territory. Furthermore, a patient described by Botez-Marquard et al. [8], another subject reported by Mari¨en et al. [9] and two patients described by Schmahmann and Sherman [29] all presented with significant cognitive or linguistic disturbances following SCA lesions. It seems that from an anatomical point of view, there is still no consensus with regard to the functional anatomy of the cerebellum that subserves cognitive modulation. However, the symptoms observed in the CCAS are consistent with predictions derived from anatomical and neuroimaging studies, which show extensive neural circuits connecting prefrontal, temporal, posterior parietal and limbic cortices with the cerebellum [96]. According to Schmahmann [19], these anatomical subcircuits constitute the structural

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basis for functional subunits, reflecting a topographic organization of motor and cognitive functions of the cerebellum, in which the anterior cerebellar lobe is mainly involved in motor functions, while the posterior parts of the cerebellum are involved in higher cognitive modulation. However, several studies and case reports demonstrate that variability may exist with regard to the functional anatomy of the cerebellum [8,23]. 4.2. The posterior fossa syndrome (PFS) The posterior fossa syndrome (PFS) is a well-known clinical entity that usually occurs in children or adolescents with posterior fossa lesions. It consists of a broad spectrum of linguistic, cognitive and behavioral-affective disturbances [97,98]. In 1958, Daly et al. [99] for the first time described transient cerebellar mutism and associated behavioral abnormalities in a patient following posterior fossa surgery. Although posterior fossa tumor resection is the most common cause of the syndrome, patients with a traumatic [100,101], vascular [77,102] and infectious etiology [103,104] have been described as well. From a semiological point of view, transient mutism, neurobehavioral abnormalities and personality changes typically develop after a short postoperative interval of relatively normal functioning [105]. This interval varies from a few hours to a couple of days [106]. In addition, mutism is usually accompanied by behavioral and affective disturbances, such as irritability and agitation, emotional lability, depressed affect, whining and an apathetic and withdrawn attitude [97,106,107]. Although agreement exists with respect to the general characteristics of the PFS, considerable semiological diversity can be observed in reports of the PFS. The syndrome significantly varies in terms of severity and duration of symptoms as well as in its semiological expression [106,107]. Cerebellar mutism invariably constitutes the hallmark characteristic of the syndrome, but reports exist in which behavioral and affective disturbances are documented as the sole consequence of posterior fossa surgery [77,108]. Riva and Giorgi [109] for instance, identified distinct patterns of post-operative symptoms associated with cerebellar tumor localization. Tumors infiltrating the right cerebellar hemisphere were associated with difficulties in verbal processing and complex language tasks, whereas tumors of the left cerebellar hemisphere correlated with deficits in nonverbal/spatial processing. Similar observations were made by Scott et al. [110] and Siffert et al. [111]. With regard to its incidence, variable figures have been reported. In the study of Doxey et al. [98], 20 out of 253 children (8%) developed the PFS after tumor surgery. Pollack [97] recorded an incidence of 12% in a study of 142 children and Catsman-Berrevoets et al. [112] reported an incidence of 29% (12 out of 42 children). Despite extensive research, the pathophysiological substrate of the syndrome remains unclear. Several authors have held the surgical approach, usually involving the splitting of

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the vermis, responsible for the PFS [113]. However, the observation that the syndrome may follow vascular, infectious or traumatic etiology shows that non-surgical cerebellar damage might also induce the PFS. In addition, Pollack et al. [97] emphasized that the delayed onset of symptoms indicates that the responsible anatomical structures leading to the syndrome are not directly damaged during surgery and consequently may not be located in the direct area of the cerebellar midline. A second possible hypothesis explaining the PFS might be the involvement of the dentate nucleus [107]. The dentate nucleus is reciprocally connected with the ventrolateral part of the thalamus (dentato-rubro-thalamic tract) which has well-established connections with the supplementary motor area (SMA) [114]. This cortical area is known to be involved in motor speech control and when damaged, might induce mutism [114]. In addition, lesions of the ventrolateral thalamic nucleus might also lead to mutism [115]. As a result, the dentato-thalamo-cortical pathway connects these anatomic structures in a common circuit that might be crucially involved in the pathophysiology of mutism. Consequently, structural damage to one of the composite structures within this circuit might result in mutism [116]. However, results are not consistent. Asamoto et al. [117] for instance reported two patients with cerebellar mutism, without any abnormalities in the dentate nuclei. In addition, a number of alternative pathophysiological hypotheses have been introduced to explain the condition, such as post-operative tissue swelling or oedema [97], post-operative vasospasms [118], surgical manipulation of the brainstem [119], post-operative hydrocephalus and meningeal reactions [120] and dysfunction of the neurons of the A9 to A10 dopaminergic cell group [121]. However, none of these hypotheses can sufficiently account for the broad spectrum of symptoms of the PFS [97]. One of the most recent hypothetical explanations for the PFS is the phenomenon of cerebello-cerebral diaschisis. This phenomenon represents the metabolic impact of a cerebellar lesion in a distant but anatomically and functionally connected supratentorial region [9,84]. Although the phenomenon of cerebellar-cerebral diaschisis has been advanced to explain neurobehavioral alterations and cognitive dysfunctions following focal cerebellar damage in children and adults [9,84], results are not uniform. Ersahin et al. [122] for instance, did not find any significant differences in blood-flow distribution in children with and without mutism.

5. Conclusion As a result of the abundantly clear and extensively documented role of the cerebellum in motor functioning, the involvement of the cerebellum in cognitive and affective modulation has been overlooked for a very long time. Research from the past two decades has convincingly extended insights into the role of the cerebellum. In the early literature, cognitive symptoms and behavioral abnormalities, such as mental retardation, aberrant behavior and even psychosis, were fre-

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quently, but anecdotally mentioned in patients with cerebellar diseases, such as cerebellar agenesis [86], cerebellar atrophy [123] and cerebellar ataxia [124]. Despite these observations, the study on cerebellar functioning during the 20th century remained dominated by the role of the cerebellum in coordination and motor control. However, in 1978 Watson [125] provided a detailed review of a possible cerebellar involvement in non-motor functions, such as sensory processing, learning and emotion. In support of this new path of research, neuroanatomical findings and neuroimaging data described a complex network between the deep cerebellar nuclei and associative regions of the cortex involved in cognitive control and affective modulation. However, despite some overwhelming evidence, the functional role of the cerebellocerebral network still evokes many questions. An important question that remains unsolved is the precise nature of cerebellar involvement in cognitive processing. One hypothesis states that the influence of the cerebellum on cognitive regulation is not domain-specific, but generally subserving timing processes and temporal regulation [126]. Evidence to support this hypothesis was presented by clinical data of patients with cerebellar lesions who are impaired in the judgment of the duration of an auditory stimulus and the velocity of a moving visual stimulus [126,127]. In addition, patients with cerebellar lesions may experience severe distortions during duration-discrimination tasks, suggesting a critical role of the cerebellum in the representation of temporal information [128–130]. Moreover, functional neuroimaging studies in healthy subjects have shown cerebellar activation in a variety of timing tasks, suggesting a crucial role of the cerebellum in timing judgment tasks [131], in computing temporal aspects of incoming sensory stimuli and outgoing movements [132], in memory-timed finger movements [133] and in the estimation of longer time intervals [134]. However, results are inconsistent. In a recent study by Stevens et al. [135], functional circuits for mental timekeeping were identified. Functional MRI data were obtained in 31 healthy adult subjects during the performance of various timing tasks. Results showed a fronto-striatal neural timing circuit, including the anterior cingulate gyrus, the supplementary motor area, the bilateral anterior insula, the bilateral putamen, the bilateral thalamus, the right superior temporal gyrus and the supramarginal gyrus. Small areas in the right cerebellar hemisphere were activated during some of the tasks. According to the authors, their results suggest that the cerebellum is important in timing mechanisms, but is not the primary substrate of mental timing tasks [135]. Another hypothesis states that cerebellar involvement in cognitive modulation may be established through the cerebello-cerebral network, as reflected by the phenomenon of (crossed) cerebello-cerebral diaschisis in patients with cerebellar lesions. Cerebello-cerebral diaschisis reflects the functional impact of a cerebellar lesion on a distant, but anatomically and functionally connected supratentorial region. The structural cerebellar lesion causes a disturbance or reduction of the excitatory impulses from deep cerebellar

Fig. 3. Quantified ECD-SPECT study in an adult patient 5 weeks poststroke showing hypoperfusion in the right cerebellar hemisphere and the left medial frontal area. Clinically the patient presented with CCAS (adapted from Mari¨en et al. [136], [137]).

nuclei through dentatothalamic connections to the cortical areas subserving cognitive processes. Data in support of this hypothesis are derived from SPECT studies, evidencing perfusional deficits in cortical areas which are crucially involved in cognitive functioning. Cortical hypoperfusional deficits in the anatomoclinically expected regions in patients with cerebellar lesions have been reported in various studies and case reports [9,77,81,84]. Fig. 3 demonstrates the phenomenon of crossed cerebello-cerebral diaschisis in an adult patient with a cerebellar infarct in the SCA region. Following the stroke, the patient presented with the CCAS associated with perfusion deficits in the right cerebellum and the left medial frontal area (adapted from Mari¨en et al. [136]. A final point of interest in this relatively new domain of research can be found in the prognosis of cognitive deficits following cerebellar damage. As a result of the novelty of this research topic, little is known about the long-term cognitive outcome. Richter et al. [137] investigated the longitudinal outcome of cognitive dysfunctions in patients with cerebellar lesions. The authors examined the cognitive status of 21 cerebellar patients with an average of 46 months after onset of a cerebellar stroke. Their results indicated full recovery of cognitive disorders, except for distinct impairments in verbal fluency. In addition, Schweizer et al. [138] for the first time extensively investigated the rehabilitation process of a patient with a severe dysexecutive syndrome following a cerebellar arteriovenous malformation rupture. Intensive rehabilitation was carried out by means of the “Goal Management Training”-program, which consists of a therapeutic approach relying on verbally mediated metacognitive strategies specifically for executive and attentional impairments. At clinical follow-up after approximately 1 year post-stroke, the patient’s executive deficits had completely resolved. However, not all reports support the overall positive prognosis following cerebellar lesions. Baillieux et al. [77] reported persistent executive dysfunctions and behavioral abnormalities in an adolescent patient following posterior fossa tumor resection. Similar observations of persistent minor cognitive deficits were reported by Neau et al. [23] and Fabbro et al. [24]. However, in order to determine the precise outcome of cognitive dysfunctioning following cerebellar damage, controlled longitudinal follow-up studies are necessary. Many questions regarding the role of the cerebellum in cognition remain unanswered. Results from neuroanatomical, neuroimaging and clinical studies should be combined

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to disentangle the mysteries of this impressive structure at the bottom of the brain.

Acknowledgements This study was supported by grant G.0209.05 of the Fund for Scientific Research – Flanders (F.W.O. – Vlaanderen), by Onderzoeksraad (OZR-VUB), by Nationale Vereniging tot Steun aan Gehandicapte Personen (NVSG-ANAH), by Stichting Integratie Gehandicapten (SIG) and by Deloitte Belgium.

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