Oculomotor deficits affect neuropsychological performance in oculomotor apraxia type 2.

INTRODUCTION: Ataxia with oculomotor apraxia type 2 is a rare and early-disabling neurodegenerative disease, part of a subgroup of autosomal recessive cerebellar ataxia, in which oculomotor symptoms (e.g., increased saccade latency and hypometria) and executive function deficits have been described. The aim of this study was to evaluate the impact of oculomotor symptoms on cognitive performance and, in particular, over reading in 2 Italian siblings affected by ataxia with oculomotor apraxia type 2. METHODS: The neuropsychological profiles and the oculomotor patterns during nonverbal and verbal tasks were recorded and analyzed. RESULTS: Saccadic intrusions and/or nystagmus were observed in all eye movement tasks. The neuropsychological profiles were substantially preserved, with only subtle deficits that affected visuomotor integration and attention. Reading ability decreased and became impaired. The reading scan was disturbed by saccadic intrusions and/or nystagmus. However, an ad hoc reading task demonstrated that deficits appeared only when the items that were displayed enhanced oculomotor requests. The preservation of lexical-semantic processes confirmed that the reading disability was caused by oculomotor deficits, not cognitive problems. CONCLUSION: Present findings indicate that in patients who are affected by ataxia with oculomotor apraxia type 2, performance on neuropsychological tests, especially those that require rapid performance and eye or hand-eye control, must be analyzed with respect to oculomotor components.

The cerebellar cognitive profile.

The cerebellar role in non-motor functions is supported by the clinical finding that lesions confined to cerebellum produce the cerebellar cognitive affective syndrome. Nevertheless, there is no consensus regarding the overall cerebellar contribution to cognition. Among other reasons, this deficiency might be attributed to the small sample sizes and narrow breadths of existing studies on lesions in cerebellar patients, which have focused primarily on a single cognitive domain. The aim of this study was to examine the expression of cerebellar cognitive affective syndrome with regard to lesion topography in a large group of subjects with cerebellar damage. We retrospectively analysed charts from patients in the Ataxia Lab of Santa Lucia Foundation between 1997 and 2007. Of 223 charts, 156 were included in the study, focusing on the importance of the cerebellum in cognition and the relevance of lesion topography in defining the cognitive domains that have been affected. Vascular topography and the involvement of deep cerebellar nuclei were the chief factors that determined the cognitive profile. Of the various cognitive domains, the ability to sequence was the most adversely affected in nearly all subjects, supporting the hypothesis that sequencing is a basic cerebellar operation.

State estimation, response prediction, and cerebellar sensory processing for behavioral control.

State estimation has emerged as the keystone in determining the cerebellar contribution to motor control. Clinical, experimental, and neuroimaging data converge to focus on cerebellar multisensory information processing as the mechanism allowing to correctly establish the body state needed for movement. Further, recent data indicate the cerebellum specifically involved in predicting body state changes. The present editorial discusses these evidences and questions cerebellar state estimation in the cognitive domain.

Cerebellum and detection of sequences, from perception to cognition.

The idea that cerebellar processing is required in a variety of cognitive functions is well accepted in the neuroscience community. Nevertheless, the definition of its role in the different cognitive domains remains rather elusive. Current data on perceptual and cognitive processing are reviewed with special emphasis on cerebellar sequencing properties. Evidences, obtained by neurophysiological and neuropsychological lesion studies, converge in highlighting comparison of temporal and spatial information for sequence detection as the key stone of cerebellar functioning across modalities. The hypothesis that sequence detection might represent the main contribution of cerebellar physiology to brain functioning is presented and the possible clinical significance in cerebellar-related diseases discussed.

Phonological short-term store impairment after cerebellar lesion: a single case study.

The cerebellum is a recent addition to the growing list of cerebral areas involved in the multifaceted structural system that sustains verbal working memory (vWM), but its contribution is still a matter of debate. Here, we present a patient with a selective deficit of vWM resulting from a bilateral cerebellar ischemic lesion. After this acute event, the patient had impaired immediate and delayed word-serial recall and auditory-verbal delayed recognition. The digit span, however, was completely preserved. To investigate the cerebellar contribution to vWM, four experiments addressing the function of different vWM phonological loop components were performed 18 months after the lesion, and results were compared with normative data or, when needed, with a small group of matched controls. In Experiment 1, digit span was assessed with different presentation and response modalities using lists of digits of varying lengths. In Experiment 2, the articulatory rehearsal system was analyzed by measurement of word length and articulatory suppression effects. Experiment 3 was devoted to analyzing the phonological short-term store (ph-STS) by the recency effect, the phonological similarity effect, short-term forgetting, and unattended speech. Data suggested a possible key role of the semantic component of the processed material, which was tested in Experiment 4, in which word and nonword-serial recall with or without interpolating activity were analyzed. The patient showed noticeably reduced scores in the tasks that primarily or exclusively engaged activity of the ph-STS, namely those of Experiment 3, and good performance in the tests that investigated the recirculation of verbal information. This pattern of results implicates the ph-STS as the cognitive locus of the patient's deficit. This report demonstrates a cerebellar role in encoding and/or strengthening the phonological traces in vWM.

Cerebellar information processing and visuospatial functions.

Although there are consistent reports of altered visuospatial abilities in subjects with cerebellar pathologies, and although experimental evidence indicates the importance of this part of the brain in spatial processing, the role of the cerebellum in this area remains elusive. In the present essay, experimental and clinical studies from our group, focussing relations between cerebellum and visuospatial functions are reviewed. Explorative behaviour, visuospatial abilities and sequential spatial processing functions are analyzed to focus cerebellar involvement in spatial data processing. Reviewed evidence enlightens the importance of the cerebellum for scanning sensory data to extract relevant spatial information and for the acquisition of spatial-related procedures. This hypothesis is discussed within the general framework of cerebellar involvement in cognition.

The cerebellum and neural networks for rhythmic sensorimotor synchronization in the human brain.

Sensorimotor synchronization (SMS) is the rhythmic synchronization between a timed sensory stimulus and a motor response. This rather simple function requires complex cerebral processing whose basic mechanisms are far from clear. The importance of SMS is related to its hypothesized relevance in motor recovery following brain lesions. This is witnessed by the large number of studies in different disciplines addressing this issue. In the present review we will focus on the role of the cerebellum by referring to the general modeling of SMS functioning. Although at present no consensus exists on cerebellar timekeeping function it is generally accepted that cerebellar input and output flow process time information. Reviewed data are considered within the framework of the 'sensory coordination' hypothesis of cerebellar functioning. The idea that timing might be within the parameters that are under cerebellar control to optimize cerebral cortical functioning is advanced.

NMDA receptor activity in learning spatial procedural strategies I. The influence of hippocampal lesions.

To acquire knowledge about the environment two types of learning are necessary: declarative localizatory learning about where environmental cues and the subject are, and procedural learning about how to explore and move around the environment. Experimental data indicate that hippocampal regions are involved in spatial learning, playing a key role in building spatial cognitive maps. The contribution of hippocampal NMDA receptors to spatial functions is indicated by the disruption of place learning when NMDA long-term potentiation is blocked. Conversely, the hippocampal contribution to the acquisition of procedural strategies is still controversial. Inactivation of the hippocampus by antagonizing the activity of AMPA/kainate receptors results in impaired spatial procedural learning. However, in the presence of a blockade of NMDA long-term potentiation in hippocampal areas it is still possible to learn explorative strategies. To investigate the involvement of the hippocampal NMDA receptors in spatial procedural learning, an NMDA receptor antagonist (CGS 19755) was administered i.p. to unlesioned animals or to animals with total ablation of hippocampal structures that had been tested in the Morris water maze. The CGS administration induced peripheral circling in both unlesioned control animals and in rats with bilateral hippocampal ablation. Conversely, circling was not observed if the drug-treated animals (either unlesioned or lesioned) had been spatially trained before drug administration. These findings indicate that even in the absence of the hippocampal formation the NMDA receptor antagonist found a site of action to influence the acquisition of spatial procedures to search for the platform.

NMDA receptor activity in learning spatial procedural strategies II. The influence of cerebellar lesions.

Experimental data support the involvement of cerebellar circuits in the acquisition of spatial procedural competences. Since the ability to acquire new procedural competences is lost when cerebellar regions are lesioned or when NMDA receptor activity is blocked, we analyzed whether the learning of explorative strategies is affected by blocking NMDA receptor activity in the presence of cerebellar lesions. To this aim, the NMDA receptor antagonist (CGS 19755, 7 mg/kg) was administered i.p. to un-lesioned rats, or rats subjected to total ablation of the cerebellum or to hemi-cerebellectomy. CGS 19755 and cerebellectomy both produced water maze behavior characterized by circling. Administration of CGS 19755 did not modify the Morris Water Maze (MWM) peripheral circling behavior of cerebellectomized animals. Circling was the dominant strategy of hemicerebellectomized animals in the absence of drugs. However, increasingly compulsive circling was observed under the action of CGS 19755. Circling was not observed if the drug-treated animals (un-lesioned or lesioned) had been previously trained. In conclusion, the NMDA antagonist caused severe impairment in the acquisition of spatial procedures, thus mimicking the consequences of cerebellar ablation on spatial procedural learning. Based on the present findings, we hypothesize that cerebellar NMDA receptor activity is involved in the acquisition of procedural spatial competence.

The NMDA receptor antagonist CGS 19755 disrupts recovery following cerebellar lesions.

PURPOSE: To test whether activation of NMDA receptors is required for the maintenance of the posture and motor behavior recovered from cerebellar lesions, an NMDA antagonist (CGS 19755) was systemically administered to totally or partially cerebellectomized rats. METHODS: Three groups of animals were tested: rats that had undergone a total cerebellectomy four months before drug administration; rats that had undergone a right hemicerebellectomy four months before drug administration; intact control animals. RESULTS: Under drug action in the control animals the postural pattern was slightly influenced, showing a light worsening, and motor skills requiring coordinated motor performance and subtle balance control were markedly worsened. Conversely, in the lesioned groups the cerebellar symptomatology dramatically worsened, and both groups of animals looked like they had just been operated, exhibiting the whole repertoire of postural and motor behaviors of cerebellar origin. In particular, limb hyperflexion, wide-based locomotion and the tendency to side falls were prevalent in the cerebellectomized animals, while tremor and body tilt were prevalent in the hemicerebellectomized group. CONCLUSION: The reappearance of severe postural and motor symptomatology has to be interpreted as a "decompensation" evoked by the NMDA-receptor antagonist, suggesting the involvement of NMDA receptors in the maintenance of compensation of disturbances of cerebellar origin.

Sensorimotor transduction of time information is preserved in subjects with cerebellar damage.

The cerebellar contribution to motor entrainment through rhythmic auditory stimuli was analyzed by comparing rhythmic motor responses in subjects with cerebellar pathologies and in healthy controls. Eleven patients with cerebellar lesions and eight healthy subjects tapped in synchrony with an auditory rhythmic stimulus using a hand-held pencil-shaped electrode connected to a PC. A 60-stimulus sequence was delivered with an ISI of 500 ms and changed at random to a new ISI value with either consciously perceived (+/-50 ms) or unperceived tempo changes (+/-10 ms). Synchronization patterns for both groups were computed based on the timing of inter-response intervals (IRIs) and synchronization errors (SE). Variability of IRI as well as the timing of adaptation patterns after the tempo changes were modeled and analyzed mathematically using a logistic/sigmoid function. Healthy subjects performed with significantly lower IRI variability than cerebellar patients. Patients with focal lesions performed with significantly lower IRI variability than patients with atrophic lesions. Asymptote parameters during isochronous synchronization as well as slope angles and symmetry points of the adaptation curves after tempo perturbation showed no significant differences between groups. Present data indicate that temporal variability of rhythmic motor responses is differentially affected by distinct cerebellar pathologies but that motor entrainment to auditory rhythms is not affected by lesion of the cerebellar circuits.

Neurobiology of rhythmic motor entrainment.

Timing is extremely important for movement, and understanding the neurobiological basis of rhythm perception and reproduction can be helpful in addressing motor recovery after brain lesions. In this quest, the science of music might provide interesting hints for better understanding the brain timing mechanism. The report focuses on the neurobiological substrate of sensorimotor transformation of time data, highlighting the power of auditory rhythmic stimuli in guiding motor acts. The cerebellar role of timing is addressed in subjects with cerebellar damage; subsequently, cerebellar timing processing is highlighted through an fMRI study of professional musicians. The two approaches converge to demonstrate that different levels of time processing exist, one conscious and one not, and to support the idea that timing is a distributed function. The hypothesis that unconscious motor responses to auditory rhythmic stimuli can be relevant in guiding motor recovery and modulating music perception is advanced and discussed.

A new paradigm to analyze observational learning in rats.

A new paradigm of learning was developed through observational training in which rats repeatedly observed companion rats performing different spatial tasks. Observer animals were separately housed in small cages suspended over a water maze tank. They repeatedly observed companion actor rats performing spatial tasks differing according to the experimental requirements. After the observational training, observer animals were or not surgically hemicerebellectomized. This surgical ablation was performed to block any further acquisition of new behavioral strategies during actual performance of swimming task. When cerebellar symptomatology stabilized, observer animals were actually tested in the Morris Water Maze (MWM) task they had previously only observed. The observer rats displayed exploration abilities that closely matched the previously observed behaviors. The results obtained indicate that it is possible to learn complex behavioral strategies by observation using this new protocol. Furthermore, acquisition of the single facets that form the behavioral repertoire can be separately studied.

Watch how to do it! New advances in learning by observation.

Recent data demonstrate that the cerebellum contributes to the internal representation of action. This representation is used not only to generate motor actions, but also to understand and learn the actions and skills of others by imitation. The cerebellar networks appear to be indispensable for acquiring complex behaviors and procedures. The cerebellar role in the acquisition of procedural competencies is particularly evident in spatial information processing. The cerebellum allows acquiring by observation competencies in exploration behaviors as efficient as the competencies acquired by actually performing the same task. The specificity of the cerebellar role in the acquisition phases of learning by observation is demonstrated by the complete absence of spatial learning when the observational training is performed in presence of a cerebellar lesion. This datum is further corroborated by the evidence that, once acquired, spatial procedures can be efficiently performed even in the presence of cerebellar damage, in agreement with the neuroimaging findings of low cerebellar activation after prolonged practice. The finding that the cerebellum is involved in procedural acquisition and in observational learning allowed us to dissect a complex behavior into single behavioral units forming a complete procedural sequence, demonstrating that such behavioral units do exist and can be independently acquired.