Cerebellar engagement in the attachment behavioral system.

Brain structural bases of individual differences in attachment are not yet fully clarified. Given the evidence of relevant cerebellar contribution to cognitive, affective, and social functions, the present research was aimed at investigating potential associations between attachment dimensions (through the Attachment Style Questionnaire, ASQ) and cerebellar macro- and micro-structural measures (Volumetric and Diffusion Tensor Imaging data). In a sample of 79 healthy subjects, cerebellar and neocortical volumetric data were correlated with ASQ scores at the voxel level within specific Regions Of Interest. Also, correlations between ASQ scores and age, years of education, anxiety and depression levels were performed to control for the effects of sociodemographic and psychological variables on neuroimaging results. Positive associations between scores of the Preoccupation with Relationships (ASQ subscale associated to insecure/anxious attachment) and cortical volume were found in the cerebellum (right lobule VI and left Crus 2) and neocortex (right medial OrbitoFrontal Cortex, OFC) regions. Cerebellar contribution to the attachment behavioral system reflects the more general cerebellar engagement in the regulation of emotional and social behaviors. Cerebellar properties of timing, prediction, and learning well integrate with OFC processing, supporting the regulation of attachment experiences. Cerebellar areas might be rightfully included in the attachment behavioral system.

Consensus Paper. Cerebellar Reserve: From Cerebellar Physiology to Cerebellar Disorders.

Cerebellar reserve refers to the capacity of the cerebellum to compensate for tissue damage or loss of function resulting from many different etiologies. When the inciting event produces acute focal damage (e.g., stroke, trauma), impaired cerebellar function may be compensated for by other cerebellar areas or by extracerebellar structures (i.e., structural cerebellar reserve). In contrast, when pathological changes compromise cerebellar neuronal integrity gradually leading to cell death (e.g., metabolic and immune-mediated cerebellar ataxias, neurodegenerative ataxias), it is possible that the affected area itself can compensate for the slowly evolving cerebellar lesion (i.e., functional cerebellar reserve). Here, we examine cerebellar reserve from the perspective of the three cornerstones of clinical ataxiology: control of ocular movements, coordination of voluntary axial and appendicular movements, and cognitive functions. Current evidence indicates that cerebellar reserve is potentiated by environmental enrichment through the mechanisms of autophagy and synaptogenesis, suggesting that cerebellar reserve is not rigid or fixed, but exhibits plasticity potentiated by experience. These conclusions have therapeutic implications. During the period when cerebellar reserve is preserved, treatments should be directed at stopping disease progression and/or limiting the pathological process. Simultaneously, cerebellar reserve may be potentiated using multiple approaches. Potentiation of cerebellar reserve may lead to compensation and restoration of function in the setting of cerebellar diseases, and also in disorders primarily of the cerebral hemispheres by enhancing cerebellar mechanisms of action. It therefore appears that cerebellar reserve, and the underlying plasticity of cerebellar microcircuitry that enables it, may be of critical neurobiological importance to a wide range of neurological/neuropsychiatric conditions.

Cerebellar Structural Variations in Subjects with Different Hypnotizability.

Hypnotizability-the proneness to accept suggestions and behave accordingly-has a number of physiological and behavioral correlates (postural, visuomotor, and pain control) which suggest a possible involvement of cerebellar function and/or structure. The present study was aimed at investigating the association between cerebellar macro- or micro-structural variations (analyzed through a voxel-based morphometry and a diffusion tensor imaging approach) and hypnotic susceptibility. We also estimated morphometric variations of cerebral gray matter structures, to support current evidence of hypnotizability-related differences in some cerebral areas. High (highs, N = 12), and low (lows, N = 37) hypnotizable healthy participants (according to the Stanford Hypnotic Susceptibility Scale, form A) were submitted to a high field (3 T) magnetic resonance imaging protocol. In comparison to lows, highs showed smaller gray matter volumes in left cerebellar lobules IV/V and VI at uncorrected level, with the results in left lobule IV/V maintained also at corrected level. Highs showed also gray matter volumes smaller than lows in right inferior temporal gyrus, middle and superior orbitofrontal cortex, parahippocampal gyrus, and supramarginal parietal gyrus, as well as in left gyrus rectus, insula, and middle temporal cortex at uncorrected level. Results of right inferior temporal gyrus survived also at corrected level. Analyses on micro-structural data failed to reveal any significant association. The here found morphological variations allow to extend the traditional cortico-centric view of hypnotizability to the cerebellar regions, suggesting that cerebellar peculiarities may sustain hypnotizability-related differences in sensorimotor integration and emotional control.

Explorative function in Prader-Willi syndrome analyzed through an ecological spatial task.

This study was aimed at evaluating the spatial abilities in individuals with Prader-Willi syndrome (PWS) by using an ecological large-scale task with multiple rewards. To evaluate the extent of spatial deficit in PWS individuals, we compare their performances with those of individuals with Williams Syndrome (WS) in which the spatial deficits have been widely described. Participants had to explore an open space to search nine rewards placed in buckets arranged according to three spatial configurations: a Cross, a 3×3 Matrix and a Cluster composed by three groups of three buckets each. PWS individuals exhibited an explorative deficit in Cluster and Cross configurations, while WS participants in Matrix and Cross configurations. The findings indicate that the structural affordances of the environment influence the explorative strategies and can be related to how spatial information is processed.

Activity-dependent structural plasticity of Purkinje cell spines in cerebellar vermis and hemisphere.

The environmental enrichment (EE) paradigm is widely used to study experience-dependent brain plasticity. In spite of a long history of research, the EE influence on neuronal morphology has not yet been described in relation to the different regions of the cerebellum. Thus, aim of the present study was to characterize the EE effects on density and size of dendritic spines of Purkinje cell proximal and distal compartments in cerebellar vermian and hemispherical regions. Male Wistar rats were housed in an enriched or standard environment for 3.5 months from the 21st post-natal day onwards. The morphological features of Purkinje cell spines were visualized on calbindin immunofluorescence-stained cerebellar vermian and hemispherical sections. Density, area, length and head diameter of spines were manually (ImageJ) or automatically (Imaris) quantified. Results demonstrated that the Purkinje cell spine density was higher in enriched rats than in controls on both proximal and distal dendrite compartments in the hemisphere, while it increased only on distal compartment in the vermis. As for spine size, a significant increase of area, length and head diameter was found in the distal dendrites in both vermis and hemisphere. Thus, the exposure to a complex environment enhances synapse formation and plasticity either in the vermis involved in balance and locomotion and in the hemisphere involved in complex motor adaptations and acquisition of new motor strategies. These data highlight the importance of cerebellar activity-dependent structural plasticity underling the EE-related high-level performances.

Learning by observation in children with autism spectrum disorder.

BACKGROUND: Observing another person performing a complex action accelerates the observer's acquisition of the same action and limits the time-consuming process of learning by trial and error. Learning by observation requires specific skills such as attending, imitating and understanding contingencies. Individuals with autism spectrum disorder (ASD) exhibit deficits in these skills. METHOD: The performance of 20 ASD children was compared with that of a group of typically developing (TD) children matched for chronological age (CA), IQ and gender on tasks of learning of a visuomotor sequence by observation or by trial and error. Acquiring the correct sequence involved three phases: a detection phase (DP), in which participants discovered the correct sequence and learned how to perform the task; an exercise phase (EP), in which they reproduced the sequence until performance was error free; and an automatization phase (AP), in which by repeating the error-free sequence they became accurate and speedy. RESULTS: In the DP, ASD children were impaired in detecting a sequence by trial and error only when the task was proposed as first, whereas they were as efficient as TD children in detecting a sequence by observation. In the EP, ASD children were as efficient as TD children. In the AP, ASD children were impaired in automatizing the sequence. Although the positive effect of learning by observation was evident, ASD children made a high number of imitative errors, indicating marked tendencies to hyperimitate. CONCLUSIONS: These findings demonstrate the imitative abilities of ASD children although the presence of imitative errors indicates an impairment in the control of imitative behaviours.

Explorative function in Williams syndrome analyzed through a large-scale task with multiple rewards.

This study aimed to evaluate spatial function in subjects with Williams syndrome (WS) by using a large-scale task with multiple rewards and comparing the spatial abilities of WS subjects with those of mental age-matched control children. In the present spatial task, WS participants had to explore an open space to search nine rewards placed in buckets arranged according to three spatial configurations: a cross, a 3 × 3 matrix and a cluster composed by three groups of three buckets each. The findings demonstrate that WS individuals were impaired in efficiently exploring the environment and in building cognitive spatial maps. In exploring the three spatial configurations, they performed worse than control subjects on all parameters analyzed. In fact, WS individuals took more time to complete the task, made more errors, performed a reduced number of error-free trials, displayed lower search efficiency, exhibited shorter spatial spans, showed a higher number of no-visits and displayed marked tendencies to perseverate and to neglect some buckets. Furthermore, WS individuals showed disorganized explorative patterns in comparison to control children. WS influenced performances differentially as a specific effect of the susceptibility of the configurations to being explored in a principled way. In the cross configuration that had strong spatial constraints, both groups exhibited their worst performances. In the matrix configuration, the altered explorative strategies of the WS subjects primarily affected their central exploration. The performances in the cluster configuration indicated that chunking was a strategy of strength in both TD and WS groups. In conclusion, WS individuals' deficits exhibited in the present explorative test may be considered an index of their difficulties in spatial orientation and motion perception displayed in the real world. The marked impairment in spatial information processing is discussed in neuro-anatomical alterations reported in WS.

Features of sequential learning in hemicerebellectomized rats.

Because the sequencing property is one of the functions in which cerebellar circuits are involved, it is important to analyze the features of sequential learning in the presence of cerebellar damage. Hemicerebellectomized and control rats were tested in a four-choice visuomotor learning task that required both the detection of a specific sequence of correct choices and the acquisition of procedural rules about how to perform the task. The findings indicate that the presence of the hemicerebellectomy did not affect the first phases of detection and acquisition of the sequential visuomotor task, delayed but did not prevent the learning of the sequential task, slowed down speed-up and proceduralization phases, and loosened the reward-response associative structure. The performances of hemicerebellectomized animals in the serial learning task as well as in the open field task demonstrated that the delayed sequential learning task could not be ascribed to impairment of motor functions or discriminative abilities or to low levels of motivation. The delay in sequential learning observed in the presence of a cerebellar lesion appeared to be related mainly to a delay of the automatization of the response. In conclusion, it may be advanced that, through cortical and subcortical connections, the cerebellum provides the acquisition of rapid and accurate sensory-guided sequence of responses.

Children' s radial arm maze performance as a function of age and sex.

The present study analyzes the development of the spatial abilities in children aged 36-95 months and the sex-related differences by means of the free-choice and forced-choice paradigms of the eight-arm radial maze task. Clear age-related improvements were evidenced. However, a temporal window with an abrupt acceleration of specific spatial competencies acquisition was detected. The females aged 51-58 months started the task performing about 2.5 errors and ended it performing no more than 0.5 errors. The same pattern of performance was exhibited by the males aged 59-66 months. Also in the final span the 4.5-year-old females behave as the 6-year-old males. The significant correlations between 45 degrees angles and span values in the free-choice paradigm indicated that all children tended to solve the task by employing low working memory load and by using mainly efficient procedural strategies. Furthermore, children's ability to retain earlier information was influenced by both age and sex factors as indicated by the forced-choice paradigm findings. The present findings demonstrating the earlier acquisition of spatial competencies of the females in comparison to males, could reflect differences in foraging strategies between sexes, and/or differences in the anatomo-physiological development of specific brain structures, and/or different modulating effects of sexual hormones.

Spatial competences in Williams syndrome: a radial arm maze study.

This study was aimed at evaluating spatial function in subjects with Williams syndrome by using the radial arm maze task and comparing their spatial abilities with those of mental age-matched control subjects. Two different paradigms were administered: the free-choice version for analyzing the aspects linked mainly to procedural and mnesic components, the forced-choice version for disentangling components linked to spatial working memory from the procedural ones. The findings evidenced a deficit in the acquisition of procedural competences as well as in the spatial memory processes in Williams subjects. In the free-choice paradigm, they performed worse than control subjects on all parameters analyzed. Namely, they needed more time to complete the task, did not collect all rewards, exhibited low values of the spatial span as well as low percentages of correct visits, and displayed a reduced use of the most efficient exploration strategies. Even in the forced-choice paradigm, Williams subjects made a number of errors significantly higher than control subjects. The marked impairment in spatial information processing is discussed on the light of neuro-anatomical alterations reported in Williams subjects.

Cerebellar involvement in cognitive flexibility.

The aim of the present study was to investigate whether the cerebellar structures are involved in functions requiring cognitive flexibility abilities. The flexibility of the hemicerebellectomized and control animals in learning a four-choice learning task, adapting to ever-changing response rules was investigated. While in the initial phase of the task both experimental groups exhibited similar performances, only the control animals significantly improved their performance as the sessions went by. The lack of improvement in lesioned animals' performance rendered their responses particularly defective in the final phases of the task, when conversely intact animals performed best, exploiting their "learning to learn" ability. The findings demonstrate the defective influence of the cerebellar lesion on the acquisition, not the execution, of new responses. The results underline the crucial role of the cerebellum in mediating cognitive flexibility behaviors.

Improvement of hand dexterity following motor cortex rTMS in multiple sclerosis patients with cerebellar impairment.

We tested the effects of 5-Hz repetitive transcranial magnetic stimulation (rTMS) over the motor cortex in multiple sclerosis (MS) subjects with cerebellar symptoms. rTMS improved hand dexterity in cerebellar patients (n=8) but not in healthy subjects (n=7), as detected by a significant transient reduction of the time required to complete the nine-hole pegboard task. rTMS of the motor cortex may be a useful approach to treat cerebellar impairment in MS patients.

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.

Cerebral blood flow velocity changes during meaningful and meaningless gestures--a functional transcranial Doppler study.

The aim of the study was to use functional transcranial Doppler to investigate the possibility of revealing different activation patterns during healthy subjects' performance of meaningful and meaningless actions. Mean flow velocity (MFV) changes were recorded in middle cerebral arteries (MCAs) of 26 normal subjects during a rest phase and during performance of meaningful and meaningless actions. The meaningful task consisted of pouring sugar into a cup with a teaspoon. The meaningless action was an arm movement similar to that necessary for pouring sugar in a cup but without any tool and thus without a goal. Performing actions with or without meaning was associated with different patterns of MFV changes, as documented by the triple interaction condition x performing arm x side of recording [F(1, 25)=10.977; P=0.003]. During the meaningful action, MFV in MCAs increased significantly more than during the meaningless action. During the meaningless action, the MFV increase was significantly higher in the contralateral than in the ipsilateral MCA to the arm performing the task and the meaningful action determined a bilateral MFV increase only when the task was performed with the left arm. When the same task was performed with the right arm, the MFV increase was significantly higher in the contralateral than in the ipsilateral MCA. These findings suggest that the content of an action can influence MFV changes and further confirm the usefulness of transcranial Doppler in neuropsychological investigation.

Do children with developmental dyslexia have an implicit learning deficit?

OBJECTIVE: The purpose of this study was to investigate the effects of specific types of tasks on the efficiency of implicit procedural learning in the presence of developmental dyslexia (DD). METHODS: Sixteen children with DD (mean (SD) age 11.6 (1.4) years) and 16 matched normal reader controls (mean age 11.4 (1.9) years) were administered two tests (the Serial Reaction Time test and the Mirror Drawing test) in which implicit knowledge was gradually acquired across multiple trials. Although both tests analyse implicit learning abilities, they tap different competencies. The Serial Reaction Time test requires the development of sequential learning and little (if any) procedural learning, whereas the Mirror Drawing test involves fast and repetitive processing of visuospatial stimuli but no acquisition of sequences. RESULTS: The children with DD were impaired on both implicit learning tasks, suggesting that the learning deficit observed in dyslexia does not depend on the material to be learned (with or without motor sequence of response action) but on the implicit nature of the learning that characterises the tasks. CONCLUSION: Individuals with DD have impaired implicit procedural learning.

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.

Anterograde and retrograde influence of vestibular stimulation on spatial working memory.

Rats were trained in an eight-arm radial maze to explore the apparatus in search of a food reward. After completion of the training phase, some animals were submitted to a hemicerebellectomy (HCbed group), while others were used as a control group. To study the effects of vestibular stimulation on the recall of ongoing working memory information, both groups were exposed to radial maze sessions: in the first session (no-rotation), animals were confined for 30 s to the fourth arm visited without being further manipulated; in the second session (rotation), the animals were again confined for 30 s to the fourth arm visited, while the apparatus was rotated five times around its vertical axis. The effects of these manipulations on successive visits to complete the task were assessed, as well as the solving time and kinds of errors made. Errors were significantly more frequent in the control animals during the rotation session; HCbed animals were unaffected by confinement alone or by vestibular stimulation, but showed a decreased search speed. It was concluded that vestibular input is required for an adequate functioning of the working memory system devoted to the formation and consolidation of spatial mnesic traces and that the amnesic effect due to vestibular stimulation is both anterograde and retrograde in nature.

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.