Topography of Cerebellar Deficits in Humans
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- Grimaldi, G. & Manto, M. Cerebellum (2012) 11: 336. doi:10.1007/s12311-011-0247-4
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The cerebellum is a key-piece for information processing and is involved in numerous motor and nonmotor activities, thanks to the anatomical characteristics of the circuitry, the enormous computational capabilities and the high connectivity to other brain areas. Despite its uniform cytoarchitecture, cerebellar circuitry is segregated into functional zones. This functional parcellation is driven by the connectivity and the anatomo-functional heterogeneity of the numerous extra-cerebellar structures linked to the cerebellum, principally brain cortices, precerebellar nuclei and spinal cord. Major insights into cerebellar functions have been gained with a detailed analysis of the cerebellar outputs, with the evidence that fundamental aspects of cerebrocerebellar operations are the closed-loop circuit and the predictions of future states. Cerebellar diseases result in disturbances of accuracy of movements and lack of coordination. The cerebellar syndrome includes combinations of oculomotor disturbances, dysarthria and other speech deficits, ataxia of limbs, ataxia of stance and gait, as well as often more subtle cognitive/behavioral impairments. Our understanding of the corresponding anatomo-functional maps for the human cerebellum is continuously improving. We summarize the topography of the clinical deficits observed in cerebellar patients and the growing evidence of a regional subdivision into motor, sensory, sensorimotor, cognitive and affective domains. The recently described topographic dichotomy motor versus nonmotor cerebellum based upon anatomical, functional and neuropsychological studies is also discussed.
The Clinical Anatomy of the Cerebellum
Regarding the spinal and olivary inputs, the cerebellum receives massive projections from the limbs via the spinocerebellar tracts and from the face/head via the trigeminocerebellar tracts, as well as indirect projections via the inferior olivary complex . Experimental studies have shown that the dorsal/ventral spinocerebellar tracts project to the anterior lobe and lobule VIII . The trigeminocerebellar projections terminate mainly in lobule VI, with some fibers ending in lobules V/VII/VIII [8–10]. The accessory olivary nuclei relay the spinal inputs to the same lobules and to the interpositus nuclei [7, 11], whereas the principal olivary nucleus projects mainly to lobule VII and the dentate nucleus, with little projections towards lobule VI. Interestingly, unlike for the accessory olivary nuclei, the principal olivary nucleus does not target the anterior lobe.
Facing ataxic patients, the cerebellum is conveniently divided into three sagittal areas: the vermal zone in relation with the fastigial nuclei, the intermediate cortex projecting to the interpositus nucleus and the lateral cortex projecting to dentate nuclei .
The Cerebrocerebellar System: from Nonhuman Primates to Humans
The cerebellum contains more than 50% of brain neurons. Anatomical studies have shown that the cerebellum holds 60% of all brain neurons in the mouse, 70% in the rat and macaque and up to 80% in humans [18, 19]. This high proportion raises immediately the question of the computational capacities of cerebellar circuitry. There is a general agreement that these capacities are huge [17, 19]. Still, the issue of which parameters are handled by the cerebellum remains open, especially when attempting to explain the cerebellar symptoms encountered in the clinic.
The areas of the frontal cortex linked to the cerebellar circuitry are the primary motor cortex, the premotor cortex and the prefrontal cortex. In monkeys, the densest projections to pontine nuclei which emerge from the cerebral cortex are from area 4 . Those pontine neurons project especially to lobules IV, V, VI, VIIB and VIII .
Recent studies have proposed rostro-caudal distinctions in frontal cortex activity based on the abstractness of action representations . These differences could reflect a hierarchy, with anterior frontal regions governing the information processing supervised by posterior frontal regions during the realization of abstract action goals as motor acts. Such organization has direct implications for the cerebellar circuitry, because of the segregation in the anatomical links between cerebellar areas and cerebral cortex .
It was initially supposed that the cerebellum was collecting information from multiple areas of the cerebral cortex and that efferences from the cerebellum were converging to the ventrolateral nucleus of the thalamus, projecting itself to the primary motor cortex [24, 25]. This anatomical notion was convenient to explain the roles of the cerebellum in motor control. However, this view has been challenged . The efferences of the dentate nucleus towards the cerebral cortex have been explored in details by Strick and colleagues in monkeys . The nucleus can be considered as composed of a dorsal part and a ventral part (Fig. 5). The dorsal portion (considered as a motor output channel) is primarily connected with the primary motor cortex, the dorsal premotor cortex (caudal portion), the premotor cortex (ventral part). Cerebellar projections to the primary motor cortex originate chiefly from the dentate nucleus, but a small component emerges also from the interpositus nucleus. The ventral part (considered as a nonmotor output channel) is connected in particular with the areas 46 and 9. Multiple closed-loop circuits represent a fundamental architectural feature of these cerebrocerebellar interactions [22, 25]. Although a definite confirmation that the human dentate nucleus projects to the prefrontal cortices is still missing, neuroimaging studies in humans (using diffusion tensor imaging (DTI), tractography or techniques like resting-state fluctuations) are converging towards the concept that findings in nonhuman primates and in humans are consistent. This is very attractive given the high level of analogy between the motor deficits observed in case of cerebellar lesions in monkeys and those observed in humans .
Although the emphasis is often put on the connections between the cerebellum and the frontal lobes (especially the areas 4, 6, 8, 9, 10, 11 and 46) or the parietal areas 5 and 7, other anatomical pathways should not be underestimated, such as the cortico-rubro-olivary system (relay in red nucleus and Darksewitsch nucleus) participating in closed loops with cerebral cortices, the parieto-temporal projections towards pontine nuclei, the posterior visual areas targeting the medial and lateral pons and functionally linked to the flocculonodular lobe, and the projections from motor and premotor cortex to precerebellar brainstem nuclei [1, 3, 5, 6, 20, 21].
Cerebellum, Motor Control and Nonmotor Control
There are converging evidence that cerebellar circuitry contributes actively to the regulation of cognitive operations [27, 30]. The literature of these last 2 decades highlights 4 domains for these operations: language and verbal memory, spatial tasks, executive functions and emotions [6, 17, 31–37] .
Cerebellar Deficits: Description and Topography of the Lesion
The observation of clinical deficits, the study of their anatomical distribution using high-resolution structural brain imaging and the confrontation with the anatomical studies have greatly improved the symptom-lesion mapping. Signal-to-noise ratio on magnetic resonance imaging (MRI) allows now spatial resolution in the submillimeter range, impacting on our understanding of the ataxic signs .
Motor symptoms of cerebellar lesions
Localization of lesions
Rhythmic oscillatory movements of 1 or both eyes, with a fast and a slow component in opposite directions
Uvula and nodulus
Dysmetria of saccades and saccadic pursuit
Inaccurate saccades with over/under-shooting of the target
Dorsal vermis/Fastigial nucleus
Uvula and pyramid
Fixation deficits (instability, oscillations)
Inability to maintain the eyes motionless during fixation
Abnormal gain of VOR (vestibulo-ocular reflex)
Compensative rotation during eye/head movements
Uvula and pyramid
An error in trajectory due to a disturbed range, rate and/or force of the movement
Lateral cerebellar cortex
Decomposition of movement
Decomposition of multi-joint tasks into elemental movements
Dentate nucleus and interposed nuclei
Broad-based stance with increased body sway
Medial and intermediate cerebellum
Fastigial and interposed nuclei
Irregular, broad-based and unsteady gait
Posterior inferior cerebellar vermis (abnormal tandem gait)
Explosive nasal speech with a typical scanning aspect
Superior paravermal region
Intermediate cerebellar cortex
The fastigial nucleus plays a key-role not only for eye movements, but also for the control of head position. The rostral fastigial nucleus controls head orientation and eye–head gaze shifts  whereas the caudal fastigial nucleus regulates oculomotor aspects, such as saccades or smooth pursuit . Infarcts of medial branches of the PICA (supplying mostly the inferior vermis and paravermian inferior hemispheres) are more commonly correlated with oculomotor signs (nystagmus) when compared with other cerebellar arteries infarction [45, 46]. Consistently with the animal studies, ocular motor disorders highly correlate with atrophy of the medial cerebellum in patients affected by a cerebellar degenerative disease . A study on patients affected with focal lesion in different cerebellar areas has pointed out that a medial cerebellar lesion impairs adaptation of reactive—but not of voluntary—saccades, whereas a lateral lesion affects adaptation of scanning voluntary saccades, but not of reactive saccades, providing the first evidence of an involvement of the lateral cerebellum in saccadic adaptation . A comparative study conducted on two groups of cerebellar stroke patients presenting with and without a deficient gain of smooth pursuit has confirmed that the uvula (lobule IX of the vermis) and partly the vermal pyramid (lobule VIII of the vermis) are commonly damaged in patients with deficient gain of the horizontal sinusoidal smooth pursuit eye movement, the slow phase of the optokinetic nystagmus and impaired fixation suppression of VOR . Data from surgical lesions of the nodulus and uvula in monkeys suggest a critical role of these structures in vertical pursuit, particularly for sustained downward pursuit . In his review on smooth pursuit, Sharpe has underlined that overall, the ventral paraflocculus and the caudal vermis participate in processing pursuit commands that are transmitted to the vestibular nuclei and consequently, lesions of cerebellar pursuit regions cause bidirectional, omnidirectional or ipsiversive paresis of smooth pursuit .
Cerebellar patients may present alterations of speech which is often explosive, with a staccato rhythm and a nasal character, showing a suggestive scanning aspect [51, 52]. Lesions of the superior paravermal region are commonly associated with speech deficits . It has been proposed that, as a result of asymmetric development of language, damage to the left intermediate cerebellar cortex might be one of the main causes of the cerebellar dysarthria [53–55]. Although earlier studies have suggested that left-sided lesions are followed by dysarthria , recent studies have found that lesions of both sides can be associated with dysarthria [55–58]. In particular, dysarthria is related to lesions of the dentate nucleus, paravermal and hemispheral lobules V and VI . Dysarthria is one of the signs of infarction of mSCA (medial branch of the superior cerebellar artery) territory. In degenerative disorders, speech deficits often correlate with involvement of the intermediate cerebellum .
Two separate networks might supervise speech motor control : the supplementary motor area, the dorsolateral frontal cortex including Broca area, the anterior insula and the superior cerebellum would constitute a preparative loop, whereas the executive loop would include the sensorimotor cortex, basal ganglia, thalamus and the inferior cerebellum. Mutism is described below.
Impairment in performance of limb movements—including various combinations of dysmetria, dysdiachokinesia, postural and kinetic tremor, decomposition of movement—is typical in case of cerebellar damage. As a general rule, motor deficits are lateralized to the side of the cerebellar lesion.
Action tremor is often suggestive of anterior lobe cerebellar pathology. However, it may be observed also in diffuse cerebellar diseases such as idiopathic late-onset cerebellar atrophy or hereditary dominant spinocerebellar ataxias [60–63]. Both discontinuities in movements and tremor could result from impaired stretch reflexes and disorganized servo-assistance mechanisms, with a contribution of transcortical pathways [2, 17, 61, 64]. A detailed analysis of firings of neurons has revealed that the neuronal populations discharging strongly in relation to cerebellar tremor respond markedly and reciprocally to limb perturbation. However, the 3–4 Hz cerebellar tremor is not driven by a purely central oscillator . Atrophy of the anterior lobe of the cerebellum may be associated with a very suggestive 3 Hz leg tremor in alcoholic patients (see “Posture and Gait”). The Guillain–Mollaret triangle (dentate-rubro-olivary pathway: projection of the dentate nucleus to the contralateral red nucleus and inferior olive via the superior cerebellar peduncle, the central tegmental tract and the inferior cerebellar peduncle) is presumed to play a determinant role in the genesis of oscillations involving body segments in humans, including the various combinations of action tremor, kinetic tremor and isometric tremor observed in cerebellar ataxias [2, 17].
Decomposition is a typical feature of ataxic movements and is often accompanied by an inability to generate independent finger movements. Lesions of the dentate nuclei are typically associated with an overshoot of the target (hypermetria) and a decomposition of multi-joint movements [66, 67]. For slow multi-joint movements, decomposition is manifested by errors in the direction and rate of the movement. The lack of coordination cannot be explained by a simple summation of the elemental deficits observed during single-joint movements. Deficits in adaptation of the interaction torques generated in a multi-degree of freedom human arm have been demonstrated in cerebellar patients . The intermediate zone appears to be of particular importance for multi-joint limb control in both goal-directed leg movements and in locomotion. Disorders in limb kinetic functions correlate with atrophy of lateral and intermediate parts of the cerebellum . Lesion-symptom correlation in a group of 90 patients with focal cerebellar lesion has revealed that limb ataxia is significantly correlated with lesions of the interposed and part of the dentate nuclei [59, 69]. Infarction of the lateral branches of SCA and PICA (posterior inferior cerebellar artery) often result in limb ataxia and impaired kinetic functions .
In case of cerebellar atrophy, there is a significant correlation between the degree of cerebellar degeneration and clinical rating scores of ataxia. We have found a significant correlation (a) between the severity of hypermetria in distal limb movements and the AS 20 clinical rating score  and (b) between the delayed onset latency of the antagonist muscle activity and the AS 20 clinical rating score .
Cerebellar patients with diffuse atrophy or focal lesions (stroke and tumor) involving dentate nuclei show an abolition of the short-term adaptation of anticipatory postural adjustments during bimanual actions . Patients cannot acquire the adjustments in a similar but previously untrained situation. Acquisition of a new coordination requires an intact cerebellum ipsilaterally to the postural hand, but integration of bimanual commands after a long period of consolidation is largely independent of the cerebellum .
Posture and Gait
Sitting, stance, and gait are usually impaired in midline cerebellar lesions. Lesions in the medial and intermediate zones of the cerebellum, especially in the anterior lobe, disturb movements necessarily linked to the equilibrium function . Lesions involving the fastigial and interposed nuclei are correlated with abnormal postural sways and gait ataxia. Volumetry studies in patients with degenerative cerebellar disorders show a high correlation between posture/gait ataxia clinical subscores (using a semiquantitative rating scale such as the International Cooperative Ataxia Rating Scale which is divided into four subscales including a section on postural/gait disturbances, and which is recommended in degenerative disorders of the cerebellum [38, 78]) and medial/intermediate cerebellar volume . Lesions in the posterior paravermis and nodulus are associated with lateropulsion, and lesions of the culmen (part of the rostral vermis which receives spinocerebellar projections) may cause an isolated lateropulsion .
An important role of the posterior inferior cerebellar vermis in tandem gait has been shown by Bastian and colleagues who reported an isolated abnormal tandem gait with preserved regular gait and stance in children with surgical transection of the posterior inferior cerebellar vermis . PET studies examining gait and fMRI studies on mental imagery of gait and stance have shown activation of the superior cerebellar vermis [81, 82]. A recent study, based on the voxel-based lesion-symptom mapping analysis has confirmed that lesions of superior vermis correlate with ataxia of posture (lobule III) and gait (lobules II and III). Moreover, regions correlating with lower limb ataxia are located more medially than lesions correlating with upper limb ataxia . Studies on vascular patients have shown that ataxia of stance and gait is more severe in lesions involving the mSCA and mPICA as compared with lateral SCA branch (lSCA) and lPICA infarction [83, 84].
As stated earlier, there are convincing evidence for a role of the cerebellum in cognitiveoperations, but the debate on the exact function of the cerebellum remains. The seminal paper of Leiner et al. has re-launched an old idea that the cerebellum might contribute to mental skills , and the works of Schmahmann have played a critical role in re-defining the cognitive operations under cerebellar supervision/co-supervision using modern techniques . Strong support for a cerebellar role in cognitive operations has come from functional neuroimaging studies in humans . The range of tasks associated with cerebellar activation is wide, including language functions such as verb generation, verbal working memory, and verbal fluency, visuospatial tasks (mental imagery, block design, figure drawing/copying), executive functions, emotion, pain and addiction [17, 25, 86–88]. However, although numerous tasks are associated with activations in the cerebellum, the specificity of these changes are often difficult to ascertain . In numerous situations, the cerebellar activation might be related to oculomotor behavior only .
Clinical signs of cognitive involvement are often mild and subtle, being much less pronounced than the deficits exhibited by patients with damage to cortical areas of cortico-cerebellar networks . This explains why they are often overlooked or neglected in clinical settings. Cerebellar patients often perform in the normal range of neuropsychological test norms . Deficits tend to be more detectable in case of acute cerebellar lesion, such as a cerebellar stroke, and in children with congenital disorders. However, extra-cerebellar signs, such as hydrocephalus or associated malformations, may contaminate the clinical picture.
Study on patients with PICA and SCA infarction support the hypothesis of an involvement of the right posterolateral cerebellar hemisphere (crus II) in verbal fluency . Studies in acute cerebellar stroke reveal that patients with vermal lesions maintain a significantly higher performance than patients with paravermal lesions when evaluating the understanding of hearing and total aphasia score. Understanding of reading function is significantly better in patients with small lesions compared with those with large lesions . The issue of possible memory deficits in cerebellar patients has also been raised . Tasks requiring planning/initiation, sustaining and inhibiting activity, inferring, judging and shifting set are often abnormal in inherited ataxias. Mood disorders and personality changes are not rare when carefully looked for . Lexico-semantic knowledge may be impaired in subjects with advanced spinocerebellar ataxia, suggesting that language is affected as the disorder progresses. Attentional deficits are congruent with the hypothesis of a role of the cerebellum in providing attentional resources allotted in a rapid way . Patients with focal lesions show disturbances in rapid serial visual presentation tasks . Data suggest a time-limited deficit in resource allocation during stimulus processing conditions. However, a genuine “dysmetria of attention” has not been demonstrated so far. A critical review of the topic points towards confounding factors .
Script sequencing is defined as the process allowing for recognition of appropriate spatial and temporal relations amongst relevant actions . Patients with cerebellar damage present a cognitive sequencing impairment, previously considered as a consequence of lesions involving the frontal cortex and basal ganglia circuits only. Script sequencing requires the use of both spatial and temporal informations, and cerebellar patients are impaired in both processes . Patients with left lesions perform defectively only on script sequences based on pictorial material and patients with right lesions only on script sequences requiring verbal elaboration. Such right/left and pictorial/verbal differences confirm the idea that cerebrocerebellar interactions are organized in segregated cortico-cerebellar loops in which specificity is not related to the mode of functioning, but to the characteristics of the information processed . Patients with global cerebellar atrophy tend to show impaired performances in all modalities.
The terminology of “cerebellar cognitive affective syndrome” (CCAS) includes impairment of executive functions including planning, set-shifting, abstract reasoning and working memory, deficits in visuospatial skills, linguistic deficiencies such as agrammatism, and inappropriate behavior, in absence of aphasia, apraxia or agnosia . Speech may be characterized by a vocal instability, reduced rate and monotony, complicating dysarthria [96, 97]. Anatomoclinical analysis shows that lesions of the posterior lobe of the cerebellum play a key role in the development of the cognitive deficits. Lesions in the territory of the PICA are an example, but cognitive disturbances may also appear following a lesion in the SCA territory, although rarely. The constellation of these cognitive/behavioral deficits is suggestive of a disruption of the cerebellar modulation of neural circuits that link prefrontal, posterior parietal, superior temporal and limbic structures including the amygdala, hippocampus and septum .
The posterior fossa syndrome—occurring mainly in children and adolescents after resection of a midline tumor of the cerebellum—represents another evidence of the role of cerebellum in cognitive functions. These patients show mutism, buccal and lingual apraxia, apathy and poverty of movements . Symptoms typically develop after a short postoperative interval from several hours to several days. When the lesion involves the vermis and spares the hemispheres, mutism quickly develops into dysarthria, which will improve markedly. When both the vermis and the right cerebellar hemisphere are involved, the recovery of speech is slow and speech often becomes monotonous and telegraphic, reminiscent of speech deficits found in frontal lobe lesions . Concomitant deficits are common: impairment in the shifting of attention, perseveration and difficulties in problem solving. The anatomical circuit underlying the posterior fossa syndrome is not established yet. Splitting of the vermis and lesions of the dentate nuclei have been proposed, as well as non specific postoperative tissue lesions.
Behavioral Effects of Cerebellar Lesions
The Functional Dichotomy of the Cerebellum
Sensorimotor tasks activate anterior lobe (lobule V) and adjacent lobule VI, with additional foci in lobule VIII. Motor activation is linked with activation in lobules VIIIA/B and somatosensory activation is confined to VIIIB.
The posterior lobe is involved in higher-level tasks, especially lobules VI and VII. Lobule VI and crus I are involved in language and verbal working memory, lobule VI in spatial tasks, lobules VI, crus I and VIIB in executive functions, and lobules VI, crus I and medial VII are activated during emotional processing. Language is right-lateralized, by contrast with spatial processing showing a greater left hemisphere activation. Right posterolateral cerebellum is specifically involved in noun-to-verb generation and internally generating spoken words according to specific rules [103, 104]. Language and executive tasks activate regions of crus I and lobule VII implicated in prefrontal-cerebellar loops. Emotional processing activates of the vermal lobule VII, participating in cerebellar-limbic circuitry. Functional neuroimaging investigations support the hypothesis that there is an anterior sensorimotor versus posterior cognitive/emotional dichotomy in the human cerebellum . Motor tasks are localized to the anterior lobe, with a secondary representation in lobules VIIIA/B; somatosensory tasks also involve the anterior lobe, with a secondary representation in lobule VIIIB.
This dichotomy in the regional topography of cerebellar subsystems provides an attractive substratum of research , keeping in mind that the attempt to dissociate completely the motor from the cognitive aspects of a given task may be very tricky. What has been considered in the past as a pure motor task has usually included inherent cognitive operations, subtle or not. The reverse may be true also. The analysis of the connectivity between the cerebellum and cerebral cortex with functional techniques should be interpreted to the light of the results of available anatomical data with conventional tools. Homologies with monkey studies are commonly used. The unravelling of the widespread sensorimotor, limbic and executive brain networks related to the red nucleus illustrate the complexity of the interpretation and the necessity to integrate structural and functional imaging to extract clinically relevant lessons . Further anatomical and functional studies are also required to map the cerebral cortical targets of the fastigial and interpositus nuclei, which are not fully uncovered. The clinical correlates of the biochemical compartments of the cerebellum (not discussed here) remain to be elucidated also, including the identification of the functions of the arrays of parasagittal stripes composing the transverse zones of the cortex .
The study of correlations between clinical deficit(s) in cerebellar patients and the anatomical lesion(s) has provided meaningful informations to establish a topography of deficits. Both defined focal lesions or diffuse cerebellar degeneration have been helpful for this goal, although localization remains less accurate in case of diffuse atrophy. Focal lesions have also the potential advantage to provide informations about the cerebellar cortex and/or the nuclei. Both neuroimaging studies and the experimental use of anatomical tracers have greatly contributed to the understanding of the cerebrocerebellar system. There is converging evidence of segregated pathways in the connectivity between the cerebellum, the frontal lobes and the posterior parietal cortex. Nevertheless, the substantial connectivity of the dentate nuclei with association areas of the cerebral cortex and the enormous current effort of research on “cerebellar cognitive operations” should not de-emphasize the role of the neocerebellum in sensorimotor control, keeping in mind the remarkable structural homogeneity of the cerebellum and the possibility of shared operative mechanisms below motor and nonmotor domains . Studies including patients with pure cerebellar disorders and new imaging tools such as DTI should be encouraged to extend our knowledge of the topography of cerebellar deficits.
Conflicts of interest
We have no conflicts of interest to declare.