Quantification of gray matter changes in the cerebral cortex after isolated cerebellar damage: a voxel-based morphometry study.

There is growing evidence based on behavioral and functional imaging studies about the cerebellar involvement in the modulation of cognitive functions. However, it still remains to be clarified how the cerebellum interacts with brain regions sub-serving different cognitive domains. In this study we used magnetic resonance imaging (MRI) and voxel based morphometry (VBM) to investigate changes of cerebral gray matter (GM) density in 15 patients with a focal cerebellar damage (CD) compared to 15 healthy controls. T2-weighted scans and T1-weighted volumes were collected from each subject. With the exception of the cerebellar lesion, none of the patients showed any additional brain MRI abnormality. T1-volumes were analyzed by voxel-based morphometry. Consistent with their neuropsychological abnormalities, patients with right-CD compared to controls showed a reduction of GM density mainly involving the left frontal, parietal and temporal lobes. Conversely, patients with left-CD did not show any significant neuropsychological or cerebral GM abnormality. The present study indicates that specific GM changes may be detected in patients with isolated CD and cognitive dysfunction. We discuss the findings in terms of cerebellar influence on the neuronal networks involved in higher level functions of the association cortex.

Environmental enrichment mitigates the effects of basal forebrain lesions on cognitive flexibility.

The aim of the present study was to investigate whether basal forebrain lesions were able to impair a task requiring cognitive flexibility abilities and analyzing the effect of the rearing in an enriched environment on such form of flexibility in rats with or without basal forebrain cholinergic lesions. In adult rats reared in enriched or standard conditions of the cholinergic projection to the neocortex damage was inflicted by 192 IgG-saporin injection into Ch4 region of basal forebrain. Their performance was compared with those of intact animals reared in analogous conditions in a four-choice serial learning task which taps flexibility in adapting to changing response rules. The results underlined the crucial role of the basal forebrain in mediating cognitive flexibility behaviors and revealed that the increase in social interactions, cognitive stimulation and physical activity of the rearing in enriched environment attenuated impairments caused by the cholinergic lesion. These findings demonstrate that rearing in an enriched environment can improve the ability to cope with brain damage suffered in adulthood.

Cognitive sequencing impairment in patients with focal or atrophic cerebellar damage.

Although cognitive impairment after cerebellar damage has been widely reported, the mechanisms of cerebro-cerebellar interactions are still a matter of debate. The cerebellum is involved in sequence detection and production in both motor and sensory domains, and sequencing has been proposed as the basic mechanism of cerebellar functioning. Furthermore, it has been suggested that knowledge of sequencing mechanisms may help to define cerebellar predictive control processes. In spite of its recognized importance, cerebellar sequencing has seldom been investigated in cognitive domains. Cognitive sequencing functions are often analysed by means of action/script elaboration. Lesion and activation studies have localized this function in frontal cortex and basal ganglia circuits. The present study is the first to report deficits in script sequencing after cerebellar damage. We employed a card-sequencing test, developed ad hoc, to evaluate the influence of the content to be sequenced. Stimuli consisted of sets of sentences that described actions with a precise logical and temporal sequence (Verbal Factor), sets of cartoon-like drawings that reproduced behavioural sequences (Behavioural Factor) or abstract figures (Spatial Factor). The influence of the lesion characteristics was analysed by grouping patients according to lesion-type (focal or atrophic) and lesion-side (right or left). The results indicated that patients with cerebellar damage present a cognitive sequencing impairment independently of lesion type or localization. A correlation was also shown between lesion side and characteristics of the material to be sequenced. Namely, 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. The present data support the hypothesis that sequence processing is the cerebellar mode of operation also in the cognitive domain. In addition, the presence of right/left and pictorial/verbal differences is in agreement with the idea that cerebro-cerebellar 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.

Visuospatial abilities in cerebellar disorders.

BACKGROUND: Cerebellar involvement in spatial data management has been suggested on experimental and clinical grounds. OBJECTIVE: To attempt a specific analysis of visuospatial abilities in a group of subjects with focal or atrophic cerebellar damage. METHODS: Visuospatial performance was tested using the spatial subtests of the WAIS, the Benton line orientation test, and two tests of mental rotation of objects-the Minnesota paper form board test (MIN) and the differential aptitude test (DAT). RESULTS: In the Benton line orientation test, a test of sensory analysis and elementary perception, no deficits were present in subjects with cerebellar damage. In MIN, which analyses the capacity to process bidimensional complex figures mentally, and in the DAT, which is based on mental folding and manipulation of tridimensional stimuli, subjects with cerebellar damage were impaired. CONCLUSIONS: The results indicate that lesions of the cerebellar circuits affect visuospatial ability. The ability to rotate objects mentally is a possible functional substrate of the observed deficits. A comparison between visuospatial performance of subjects with focal right and left cerebellar lesions shows side differences in the characteristics of the visuospatial syndrome. Thus cerebellar influences on spatial cognition appear to act on multiple cognitive modules.

Cerebellar contribution to spatial event processing: do spatial procedures contribute to formation of spatial declarative knowledge?

Spatial knowledge of an environment involves two distinct competencies: declarative spatial knowledge, linked to where environmental cues are and where the subject is with respect to the cues, and, at the same time, procedural spatial knowledge, linked to how to move into the environment. It has been previously demonstrated that hemicerebellectomized (HCbed) rats are impaired in developing efficient exploration strategies, but not in building spatial maps or in utilizing localizing cues. The aim of the present study was to analyse the relationships between spatial procedural and declarative knowledge by using the open field test. HCbed rats have been tested in two different protocols of the open field task. The results indicate that HCbed animals succeeded in moving inside the arena, in contacting the objects and in habituating to the new environment. However, HCbed animals did not react to environmental changes, when their impaired explorative pattern was inappropriate to the environment, suggesting that they were not able to represent a new environment because they were not able to explore it appropriately. Nevertheless, when their altered procedures were favoured by object arrangement, they detected environmental changes as efficiently as did normal rats. This finding suggests that no declarative spatial learning is possible without appropriate procedural spatial learning.

Neuronal plasticity of interrelated cerebellar and cortical networks.

The comprehension of the cerebellar physiology is rapidly changing in particular because of the demonstration of the cerebellar importance on cognition. In the present paper, recent data on cerebro cerebellar interactions is reviewed, particularly focusing on cerebellar influences over the neurophysiology of primary motor and primary sensory cortices. The cerebellar role in implicit learning and in sensory data processing is analysed and discussed. It is proposed that the cerebellum could control cortical plastic changes by modulating cortical excitability in a discrete topographic manner and that this mechanism could induce the coupling between significant sensory inputs and definite motor outputs considered as the neurobiological substrate for implicit learning.

Learning power of single behavioral units in acquisition of a complex spatial behavior: an observational learning study in cerebellar-lesioned rats.

By combining an observational spatial learning paradigm with a cerebellar lesion that blocks the acquisition of new spatial strategies, it is possible to separate a complex spatial behavior into its fundamental units to study which relationships among units have to be maintained so that the entire behavior might be acquired. Normal rats were first allowed to observe demonstrator rats performing single explorative behaviors (circling, extended searching, direct finding), then were hemicerebellectomized and, finally, tested in the Morris water maze. In spite of the cerebellar lesion, the observer rats displayed exploration abilities that closely matched the previously observed behaviors. These results indicate that the single facets that form the strategy repertoire can be independently acquired.

Cerebellar contribution to spatial event processing: involvement in procedural and working memory components.

Spatial function is one of the cognitive functions altered in the presence of cerebellar lesions. We investigated the cerebellar contribution to the acquisition of spatial procedural and working memory components by means of a radial maze. To establish whether a cerebellar lesion would cause a deficit in solving the radial maze, a first experiment was carried out by using a full-baited maze procedure in different experimental groups, with or without cerebellar lesion and with or without pretraining. Non-pretrained hemicerebellectomized (HCbed) animals exhibited impaired performances in all (motor, spatial and procedural) task aspects. Pre-trained HCbed animals performed similarly to control animals in the task aspects linked to the processing of spatial and procedural factors. To distinguish procedural from working memory components, a forced-choice paradigm of the radial maze was used in the second experiment. Non-pretrained HCbed rats continued to make a lot of errors and show severe perseverative tendencies, already observed in the first experiment, supporting a specific cerebellar role in acquiring new behaviours and in modifying them in relation to the context. Interestingly, hindered from putting the acquired explorative patterns into action and compelled to use only working memory abilities, the pretrained HCbed group exhibited a dramatic worsening of performance. In conclusion, the present findings demonstrate that cerebellar damage induces a specific behaviour in radial maze tasks, characterized by an inflexible use of the procedures (if indeed any procedure was acquired before the lesion) and by a severe impairment in working memory processes.

Phonological grouping is specifically affected in cerebellar patients: a verbal fluency study.

OBJECTIVES: Recent clinical and functional neuroimaging evidence points towards a cerebellar role in verbal production. At present it is not clear how the cerebellum participates in language production. The aim was to investigate the influence of cerebellar lesions on verbal fluency abilities with specific focus on the verbal searching strategies employed by patients with cerebellar damage. METHODS: Twenty five patients with focal or degenerative cerebellar disease and 14 control subjects were tested in a timed verbal fluency task requiring word production under forced (phonemic or semantic) conditions. To analyse the verbal searching strategy employed, semantic and phonemic cluster analyses were also performed. RESULTS: Performances of cerebellar patients were comparable with those of controls in the semantic task; conversely their performances were significantly impaired when tested in the letter task. Cluster analysis results showed that the verbal fluency impairment is linked to specific damage of phonemically related retrieval strategies. CONCLUSION: Cerebellar damage impairs verbal fluency by specifically affecting phonemic rule performances while sparing semantic rule ones. These findings underline the importance of the cerebellar computing properties in strategy development in the linguistic domain.

Representation of actions in rats: the role of cerebellum in learning spatial performances by observation.

Experimental evidence demonstrates that cerebellar networks are involved in spatial learning, controlling the acquisition of exploration strategies without blocking motor execution of the task. Action learning by observation has been considered somehow related to motor physiology, because it provides a way of learning performances that is almost as effective as the actual execution of actions. Neuroimaging studies demonstrate that observation of movements performed by others, imagination of actions, and actual execution of motor performances share common neural substrates and that the cerebellum is among these shared areas. The present paper analyzes the effects of observation in learning a spatial task, focusing on the cerebellar role in learning a spatial ability through observation. We allowed normal rats to observe 200 Morris water maze trials performed by companion rats. After this observation training, "observer" rats underwent a hemicerebellectomy and then were tested in the Morris water maze. In spite of the cerebellar lesion, they displayed no spatial defects, exhibiting exploration abilities comparable to controls. When the cerebellar lesion preceded observation training, a complete lack of spatial observational learning was observed. Thus, as demonstrated already for the acquisition of spatial procedures through actual execution, cerebellar circuits appear to play a key role in the acquisition of spatial procedures also through observation. In conclusion, the present results provide strong support for a common neural basis in the observation of actions that are to be reproduced as well as in the actual production of the same actions.

Cerebellar contribution to spatial event processing: characterization of procedural learning.

Recently, we demonstrated the prevalent role of cerebellar networks in the acquisition of the procedural components of spatial information by testing hemicerebellectomized (HCbed) rats in a classical spatial task, the Morris water maze (MWM). As procedures used in the water maze are a mixture of different components (that is, general procedures, exploration procedures, direct reaching procedures), for optimally solving a spatial task all procedural components must be opportunely managed. Thus, severely impaired procedural learning of cerebellar origin can be better comprehended by fractionating the procedural facets. To this aim, a two-step water-maze paradigm was employed. Normal rats were first trained to search for a hidden platform moved to a different position in each trial, utilizing a water maze setting in which visual cues were abolished by heavy black curtains surrounding the tank. In this paradigm, normal animals solved the task by using general and exploration procedures, but they could not use direct reaching skills. A subgroup of these pretrained animals was then HCbed and, after recovery from cerebellar lesion, was tested in a water maze with normal environmental cues available, a paradigm in which normal animals develop abilities for reaching the target with very direct trajectories. Pretrained HCbed animals, however, did not display the typical spatial deficits of naive HCbed rats, persisted in exhibiting the scanning strategy learned during pretraining, and never displayed direct reaching skills. In conclusion, cerebellar networks appear to be involved in the acquisition of all procedural facets necessary for shifting behavior within the maze until direct reaching of the platform. The lack of flexibility in changing exploration strategies displayed by pretrained HCbed rats is interpreted by taking into account the well-known cerebellar frontal interplay sculpting a specific cerebellar role in the acquisition of spatial procedural steps.

Verbal short-term store-rehearsal system and the cerebellum. Evidence from a patient with a right cerebellar lesion.

We describe an 18-year-old patient who underwent surgical removal of the right cerebellar hemisphere for the presence of a neoplastic lesion. After surgery, the patient's neuropsychological examination was normal except for a transient selective verbal short-term memory (STM) impairment characterized by reduced verbal digit span and rapid forgetting of verbal material. An extensive examination of the patient's deficit was performed in order to identify which of the two components of STM (phonological short-term store and/or rehearsal system) was impaired. The functional locus of the deficit was identified at the level of the phonological output buffer, a component of the rehearsal system, as suggested by the pattern of results obtained, namely: the improvement of the digit span seen with pointing compared with the verbal response; the advantage of auditory over visual presentation of digits; and the lack of a phonological-similarity effect with visual presentation of letters. On the other hand, the functioning of the phonological store was demonstrated by the normal amplitude of the recency effect in free recall of words and by the phonological-similarity effect with auditory presentation of letters. Our finding is consistent with previous functional (PET) studies showing the involvement of the right cerebellum during tasks requiring silent recirculation of verbal information. We conclude that the cerebellum takes part in the planning of speech production at a level that does not require an overt articulation.

The cerebellum in the spatial problem solving: a co-star or a guest star?

The experimental findings reviewed here indicate that the cerebellum has to be added to the regions known to be involved in the spatial learning. Cerebellar function is specifically linked to 'how to find an object' rather than 'where the object is in the space'. In the Morris water maze (MWM) hemicerebellectomized (HCbed) rats displayed a severe impairment in coping with spatial information, displaying only peripheral circling. And yet, when the MWM cue phase was prolonged, HCbed rats succeeded in acquiring some abilities to learn platform position, even in a pure place paradigm, such as finding a hidden platform with the starting points sequentially changed. Conversely, whether the searching strategy was acquired preoperatively, no exploration deficit appeared. Thus, cerebellar lesions appear to affect the procedural components of spatial function, sparing the declarative ones. When intact animals were non-spatially pre-trained and then HCbed, they exhibited an expanded scanning strategy, underlining the cerebellar involvement in procedural component acquisition. By testing HCbed rats in an active avoidance task, first without and then with a request for right/left discrimination, lesioned rats displayed severe deficits. Thus, besides a marked impairment in facing procedural components of spatial processing, cerebellar lesion provokes deficits also in right/left discrimination task. In conclusion, it is possible to propose the cerebellum as one part of a large system that includes frontal, posterior parietal, inferior temporal cortices, hippocampus and basal ganglia. These structures form an allocentric spatial system and an egocentric control system, that interlock to process the information involved in representing an object in the space.

Cerebellum and procedural learning: evidence from focal cerebellar lesions.

The aim of the present study was to investigate the influence of focal cerebellar lesions on procedural learning. Eight patients with cerebellar lesions and six control subjects were tested in a serial reaction-time task. A four-choice reaction-time task was employed in which the stimuli followed (or not) a sequence repeated 10 times, with the subjects aware (or not) of the item sequence. Learning was manifested by the reduction in response latency over the sequential blocks. Acquisition of declarative knowledge of the sequence was also tested. Reaction times displayed by patients with cerebellar lesions, even though they tended to be longer than those of control subjects in all testing conditions, significantly differed from control subjects only when the stimuli were presented in sequence. The reaction times in sequential trials were still statistically significant when simple motor response times were taken into account. Cerebellar patients were also significantly impaired in detecting and repeating the sequence. On the other hand, when the sequence was learned before testing, motor performances were significantly improved in all subjects. These data indicate that cerebellar lesions induce specific impairment in the procedural learning of a motor sequence and suggest a role of the cerebellar circuitry in detecting and recognizing event sequences.

Spatial dysgraphia and cerebellar lesion: a case report.

Spatial dysgraphia is a writing disorder that occurs in patients with right hemisphere lesion. We report a patient with cerebellar atrophy and spatial dysgraphia. To explain this finding, we hypothesize a discoordination between planning of the movement and performance due to a lack of the cerebellar modulation between supratentorial (premotor cortex) and peripheral (proprioceptive) afference during the ongoing handwriting movement.

Verbal fluency and agrammatism.

Since the beginning of this century it has been documented that cerebellar lesions induce speech deficits but these were thought to result from lack of motor coordination in the muscular activity needed for phonation. The pure motor nature of the cerebellum has been challenged on different grounds, and cerebellar activation has been documented in language-related tasks independently from motor activity. This chapter reviews the available evidence in favor of a cerebellar contribution to linguistic processing, focusing mainly on clinical observations in patients. The clinical findings are discussed in the light of recent theories on cerebellar functions.

Influence of disorders of visual perception in word-to-picture matching tasks in patients with Alzheimer's disease.

Patients affected by early Alzheimer's disease were given word-to-picture matching tasks in which the foils shared lexical-semantic, phonological, or visual-perceptual features with the target. The aim of the study was to evaluate the influence of the visual perceptual deficit in lexical comprehension tasks based on pictorial material. The results demonstrated that perceptual deficits are common in Alzheimer's disease. This finding is in agreement with the hypothesis that multiple modular deficits in Alzheimer's disease contribute to impaired comprehension.

Nucleus-specific expression of GABA(A) receptor subunit mRNAs in monkey thalamus.

Expression of 10 GABAA receptor subunit genes was examined in monkey thalamus by in situ hybridization using cRNA probes specific for alpha 1, alpha 2, alpha 3, alpha 4, alpha 5, beta 1, beta 2, beta 3, gamma 1, and gamma 2 subunit mRNAs. These displayed unique hybridization on patterns with significant differences from rodents. Alpha 1, beta 2, and gamma 2 transcripts were expressed at high levels in all dorsal thalamic nuclei, but expression was significantly higher in sensory relay nuclei-especially the dorsal lateral geniculate nucleus. Other transcripts showed nucleus-specific differences in levels of expression and in the range expressed. Alpha 5 and alpha 4 subunit transcripts were expressed in all nuclei except the intralaminar nuclei. Levels of alpha 2, alpha 3, beta 1, beta 3, and gamma 1 expression were very low, except in intralaminar nuclei. In the reticular nucleus, most subunit transcripts were not expressed, and only gamma 2 transcripts were consistently detected at modest levels. Thalamic GABAA receptors may be assembled from nucleus-specific groupings of subunit polypeptides.