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.

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.

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.

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.

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.

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.

Luciani's work on the cerebellum a century later.

In 1891, Luigi Luciani published his famous monograph on the cerebellum and formulated his triad of the cerebellar symptoms: atonia, asthenia and astasia, which explained all troubles provoked by cerebellar lesions; later he added a fourth sign, dysmetria. In spite of the fact that it was advanced in a pre-electrophysiological period, Luciani's interpretation of the cerebellar role in many motor functions survives more than a century later and his terminology has entered the routine of the neurological examination. With the modern knowledge of cerebellar circuitries, we can state that Luciani rightly pointed out the role of the cerebellum in regulating postural tone and muscular force, and that conversely he was wrong in denying cerebellar influence in co-ordination of multi-joint movements and the somatotopic localizations in the cerebellar cortex and nuclei. In spite of this, Luciani's work represents a milestone in cerebellar physiology.

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.

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.

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.

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.

The effect of ethanol on early manifestations of recovery from vestibular lesion.

The effect of intraperitoneal (i.p.) injection of ethanol (250 mg/kg) on compensatory rate of vestibular symptoms after unilateral labyrinthectomy was studied in guinea pigs. The treated group showed a faster dampening of vestibular disturbances in comparison with control animals. Both ocular and postural asymmetries declined to at least 50% of peak values after 2-3 h following alcohol injection. In control animals the same extent of compensation was achieved in 5-8 h after saline injection. This accelerating action of ethanol on early manifestations of vestibular compensation can be obtained by means of an increased inhibitory influence on vestibular nuclei and of an increased information provided by sensory systems.

Compensation of vestibular symptoms in hemilabyrinthectomized guinea pigs. Role of the sensorimotor activation.

The effect of sensorimotor activation on compensatory rate of vestibular asymmetries after unilateral labyrinthectomy was analyzed in guinea pigs. An intensified sensorimotor activation was obtained by putting in water the animals immediately after the appearance of hemilabyrinthectomy (HL) symptoms. The water-maintained group exhibited a faster dampening of vestibular disturbances in comparison with control animals. Both ocular and postural asymmetries declined to about 50% of peak values after 2-3 h from HL, while in control group the same extent of recovery was achieved in 4-6 h from HL. It is concluded that the generalized activation of the ascending spinal pathways carrying exteroceptive and proprioceptive information to the vestibular nuclei represents a favourable condition for the regainment of ocular and postural balance impaired by HL.

Behavioural recovery from unilateral vestibular lesion is facilitated by GM1 ganglioside treatment.

Exogenously administered gangliosides function in vivo to facilitate survival and repair of damaged neurones in both central and peripheral nervous systems. These effects have been attributed to their neuritogenic and neuronotrophic properties. In this investigation the effects of ganglioside treatment have been studied on the compensation that follows a unilateral labyrinthectomy, considering that the vestibular recovery is supposed to be achieved through a mechanism of sprouting acting on the deafferented neurones. Hemilabyrinthectomized guinea pigs were given a daily injection of either GM1 ganglioside (30 mg/kg, i.p.) or saline for 21 days. As regards postural symptoms, the GM1 group more quickly restored a posture of the head non-deviated in the horizontal plane, while the remaining postural symptomatology was not significantly affected by the treatment. Furthermore, the GM1-treated group attained more rapidly an ocular position characterized by very slow drifts (or by no drift at all), directed towards the side of the intact labyrinth. Ganglioside treatment did not reduce the severity of the initial hemilabyrinthectomy impairments and the effect of the treatment became evident with time. This result is consistent with the hypothesis that also in this model of neuronal plasticity, gangliosides act by enhancing reactive synaptogenesis on the deafferented vestibular neurones.

Hemicerebellectomy and motor behaviour in rats. III. Kinematics of recovered spontaneous locomotion after lesions at different developmental stages.

The locomotion of rats with a right hemicerebellectomy (HCb) performed in adulthood was compared by means of kinematic analysis with the locomotion of rats with a similar lesion performed on the first postnatal day. The age at which the animals received cerebellar lesion made a significant difference with respect to the locomotor strategies utilized in adulthood. During stance, neonatal operate rats showed a clear hyperextension of both hindlimbs but not of the forelimbs. Their locomotor posture was characterized by spinal flexion with the head held lower than normal. During swing, they showed a tendency towards 'high stepping'. Their steps were regular and symmetrical but hypometric. Adult lesioned animals displayed a marked extensor hypotonia, ipsilateral to the lesion during stance and a relevant hyperflexion affecting both sides, during swing. Alteration of the interlimb coordination and modified sequence of steps were also observed. Thus, a highly asymmetrical, impaired and unstable locomotion was displayed by this group of animals. The present findings demonstrate the importance of the age-at-lesion factor in determining the motor strategies in the recovery of locomotor function after HCb in the rat. This evidence is discussed in the light of the widespread anatomical remodelling already demonstrated following neonatal, but not adult, HCb in rats.

Spontaneous eye motility following a unilateral vestibular lesion.

The strong imbalance of the output of vestibular nuclei, resulting from a hemilabyrinthectomy, causes among other postural and ocular symptoms, a failure to hold a steady ocular position in the dark. In this study the time course of the spontaneous eye motility following a right hemilabyrinthectomy was analyzed. In all animals, at the first recordings, drifts of 0.8-1.0 degrees/s were present. These drifts were directed to the lesion side, then they shifted their trajectory more than once. At the final recordings, most animals exhibited very slow drifts (0.05-0.1 degrees/s) directed to the intact side suggesting an overcompensation of the initial extreme rightward deviation.

Tonic cervical influences on eye nystagmus following hemilabyrinthectomy: immediate and plastic effects.

In intact guinea pigs a passive horizontal rotation of the body about the fixed head induces compensatory ocular movements (cervico-ocular reflex). When the static neck deviation is maintained, a significant ocular displacement is observed. In acutely hemilabyrinthectomized animals, static body deviation towards the lesion side tonically alters eye nystagmus. It affects slow phase eye velocity and quick phase amplitude and frequency causing the eye to reach a less eccentric orbital position. Apart from such immediate influences, a plastic effect on eye nystagmus abatement is induced. In the animals restrained with no body-on-head deviation, abatement of nystagmus is delayed with respect to the animals restrained with 35 degrees body deviation towards the lesion side. Thus the head position signal is not only a contributing factor for the correction of postural deficits but also influences the time course of the ocular balancing process following unilateral vestibular damage.

Role of vestibular nuclei in 'optic' nystagmus.

Horizontal eye nystagmus beating towards the stimulated side ('optic' nystagmus) was evoked in 25 guinea pigs by stimulating an optic nerve. The complete ablation of the vestibular nuclear complex abolished this nystagmus. In a second group of 15 animals, the behavior of 63 vestibular neurons identified electrophysiologically was analyzed during eye nystagmus; most of these neurons responded with a tonic increase in discharge rate to stimulation of the optic nerves. Units sensitive to the direction of optic and labyrinthine nystagmus were also identified.

Neuronal activity in medial geniculate body following single semicircular canal stimulation.

Unit activity of medial geniculate body (MGB) neurons was recorded in curarized guinea pigs following separate thermal stimulation of single separate thermal stimulation of single semicircular canals. The same neurons were also tested with acoustic stimuli (clicks). Convergence on MGB units of inputs arising from several (2-6) canals was observed. Convergence of acoustic and vesticular influences was also demonstrated. After labyrinthine stimulation MGB neurons usually displayed inhibitory responses and, less frequently, activation. Clicks induced brief burst of activity. Our data indicate the existence of a wide vestibular projection in the MGB.