ABSTRACT: Eye movements are frequently considered diagnostic markers indicating involvement of the cerebellum. Impaired amplitude of saccades (saccade dysmetria), impaired gaze holding function (horizontal or downbeat nystagmus), and interrupted (choppy) pursuit are typically considered hallmarks of cerebellar disorders. While saccade dysmetria is a frequently considered abnormality, the velocity of saccades are rarely considered part of the constellation of cerebellar involvement. Reduced saccade velocity, frequently called "slow saccades" are typically seen in a classic disorder of the midbrain called progressive supranuclear palsy. It is also traditionally diagnostic of spinocerebellar ataxia type 2. In addition to its common causes, the slowness of vertical saccades is not rare in cerebellar disorders. Frequently this phenomenology is seen in multisystem involvement that substantially involves the cerebellum. In this review we will first discuss the physiological basis and the biological need for high saccade velocities. In subsequent sections we will discuss disorders of cerebellum that are known to cause slowing of saccades. We will then discuss possible pathology and novel therapeutic strategies.
Project description:Objective:Increasing evidence suggests a cerebellar contribution to modulate cognitive aspects of motor behavior and executive functions. Supporting findings come from studies on patients with neurodegenerative diseases, in which however, given the extent of the disease, the specific role of the cerebellum, could not be clearly isolated. Anti-saccades are considered a sensitive tool to test executive functions. The anti-saccade underlying neural network, consisting of different cortical areas and their downstream connections including the lateral cerebellum, has been largely clarified. To separate the role of the cerebellum with respect to other cortical structures in executive control, we compared the anti-saccade performances in two distinct cohorts of patients with cerebellar disorders (with and without cerebral cortical involvement). Methods:Eye movements during the execution of anti-saccades were recorded in 12 patients with spinocerebellar ataxia type 2 (a cortical-subcortical neurodegenerative disease), 10 patients with late onset cerebellar ataxia (an isolated cerebellar atrophy), and 34 matched controls. Results:In the anti-saccade task, besides dynamic changes already demonstrated in the pro-saccades of these patients, we found in both groups of cerebellar patients prolonged latency with larger variability than normal and increased directional error rate. Errors, however, were corrected by cerebellar patients as frequently as normal. No significant differences were found in patients with and without cortical involvement. Conclusion:Our results indicate, in a large cohort of cerebellar patients, that the cerebellum plays a critical role in the regulation of executive motor control not only, as well known, by controlling the end of a movement, but also modulating its initiation and reducing reflexive responses that would perturb voluntary actions.
Project description:The cerebellum may monitor motor commands and through internal feedback correct for anticipated errors. Saccades provide a test of this idea because these movements are completed too quickly for sensory feedback to be useful. Earlier, we reported that motor commands that accelerate the eyes toward a constant amplitude target showed variability. Here, we demonstrate that this variability is not random noise, but is due to the cognitive state of the subject. Healthy people showed within-saccade compensation for this variability with commands that arrived later in the same saccade. However, in people with cerebellar damage, the same variability resulted in dysmetria. This ability to correct for variability in the motor commands that initiated a saccade was a predictor of each subject's ability to learn from endpoint errors. In a paradigm in which a target on the horizontal meridian jumped vertically during the saccade (resulting in an endpoint error), the adaptive response exhibited two timescales: a fast timescale that learned quickly from endpoint error but had poor retention, and a slow timescale that learned slowly but had strong retention. With cortical cerebellar damage, the fast timescale of adaptation was effectively absent, but the slow timescale was less impaired. Therefore, the cerebellum corrects for variability in the motor commands that initiate saccades within the same movement via an adaptive response that not only exhibits strong sensitivity to previous endpoint errors, but also rapid forgetting.
Project description:The improvement of motor behavior, based on experience, is a form of learning that is critically dependent on the cerebellum. A well studied example of cerebellar motor learning is short-term saccadic adaptation (STSA). In STSA, information on saccadic errors is used to improve future saccades. The information optimizing saccade metrics is conveyed by Purkinje cells simple spikes (PC-SS) because they are the critical input to the premotor circuits for saccades. We recorded PC-SS of monkeys undergoing STSA to reveal the code used for improving behavior. We found that the discharge of individual PC-SS was unable to account for the behavioral changes. The PC-SS population burst (PB), however, exhibited changes that closely paralleled the qualitatively different changes of saccade kinematics associated with gain-increase and gain-decrease STSA, respectively. Gain-increase STSA, characterized by an increase in saccade duration, replicates the relationship between saccade duration and the end of the PB valid for unadapted saccades. In contrast, gain-decrease STSA, which sports normal saccade duration but reduced saccadic velocity, is characterized by a PB that ends well before the adapted saccade. This suggests that the duration of normal as well as gain-increased saccades is determined by appropriately setting the end of PB end. However, the duration of gain-decreased saccades is apparently not modified by the cerebellum because the PB signals ends too early to determine saccade end. In summary, STSA, and most probably cerebellar-dependent learning in general, is based on optimizing the shape of a PC-SS population response.
Project description:Saccadic eye movements enable fast and precise scanning of the visual field, which is partially controlled by the posterior cerebellar vermis. Textbook saccades have a straight trajectory and a unimodal velocity profile, and hence have well-defined epochs of start and end. However, in practice only a fraction of saccades matches this description. One way in which a saccade can deviate from its trajectory is the presence of an overshoot or undershoot at the end of a saccadic eye movement just before fixation. This additional movement, known as a glissade, is regarded as a motor command error and was characterized decades ago but was almost never studied. Using rhesus macaques, we investigated the properties of glissades and changes to glissade kinematics following cerebellar lesions. Additionally, in monkeys with an intact cerebellum, we investigated whether the glissade amplitude can be modulated using multiple adaptation paradigms. Our results show that saccade kinematics are altered by the presence of a glissade, and that glissades do not appear to have any adaptive function as they do not bring the eye closer to the target. Quantification of these results establishes a detailed description of glissades. Further, we show that lesions to the posterior cerebellum have a deleterious effect on both saccade and glissade properties, which recovers over time. Finally, the saccadic adaptation experiments reveal that glissades cannot be modulated by this training paradigm. Together our work offers a functional study of glissades and provides new insight into the cerebellar involvement in this type of motor error.
Project description:<h4>Background</h4>Individuals with autism spectrum disorder (ASD) show atypical scan paths during social interaction and when viewing faces, and recent evidence suggests that they also show abnormal saccadic eye movement dynamics and accuracy when viewing less complex and non-social stimuli. Eye movements are a uniquely promising target for studies of ASD as their spatial and temporal characteristics can be measured precisely and the brain circuits supporting them are well-defined. Control of saccade metrics is supported by discrete circuits within the cerebellum and brainstem - two brain regions implicated in magnetic resonance (MR) morphometry and histopathological studies of ASD. The functional integrity of these distinct brain systems can be examined by evaluating different parameters of visually-guided saccades.<h4>Methods</h4>A total of 65 participants with ASD and 43 healthy controls, matched on age (between 6 and 44-years-old), gender and nonverbal IQ made saccades to peripheral targets. To examine the influence of attentional processes, blocked gap and overlap trials were presented. We examined saccade latency, accuracy and dynamics, as well as the trial-to-trial variability of participants' performance.<h4>Results</h4>Saccades of individuals with ASD were characterized by reduced accuracy, elevated variability in accuracy across trials, and reduced peak velocity and prolonged duration. In addition, their saccades took longer to accelerate to peak velocity, with no alteration in the duration of saccade deceleration. Gap/overlap effects on saccade latencies were similar across groups, suggesting that visual orienting and attention systems are relatively spared in ASD. Age-related changes did not differ across groups.<h4>Conclusions</h4>Deficits precisely and consistently directing eye movements suggest impairment in the error-reducing function of the cerebellum in ASD. Atypical increases in the duration of movement acceleration combined with lower peak saccade velocities implicate pontine nuclei, specifically suggesting reduced excitatory activity in burst cells that drive saccades relative to inhibitory activity in omnipause cells that maintain stable fixation. Thus, our findings suggest that both cerebellar and brainstem abnormalities contribute to altered sensorimotor control in ASD.
Project description:The Zellweger spectrum disorders (ZSDs) are known to be severe disorders with onset in the newborn period or later in childhood, frequently resulting in death during childhood or adolescence. Here, we report a case of ZSD due to mutations in the PEX2 gene, with very mild phenotype. A 51-year-old Italian man was referred to us because of a clinical picture characterized by ataxia, areflexia, nystagmus, and strabismus, with childhood onset and slowly progressive course. The patient showed no cognitive impairment. Neurological examination revealed gait ataxia, dysarthria, dysmetria, areflexia, and bilateral pes cavus. Nerve conduction studies indicated a severe axonal sensorimotor polyneuropathy. Brain MRI showed marked cerebellar atrophy and absence of white matter involvement. MR spectroscopy uncovered a decreased N-acetyl aspartate peak. Biochemical analyses suggested a mild peroxisomal defect. Sequence analysis of the PEX2 gene identified two heterozygous mutations. The clinical phenotype of our patient differs from previously reported ZSD patients with PEX2 gene mutations and suggests that genetic screening of PEX2 is warranted in children and adults with otherwise unexplained autosomal recessive ataxia. MRI findings diverged from the "classic" spectrum observed in ZSDs. The moderate impairment in peroxisome biogenesis seems to affect predominantly neuronal cells in cerebellum, leading to cerebellar atrophy.
Project description:The eyes do not stay perfectly still during attempted fixation; fixational eye movements and saccadic intrusions (SIs) continuously change the position of gaze. The most common type of SI, square-wave jerks (SWJs), consists of saccade pairs that appear purely horizontal on clinical inspection: the first saccade moves the eye away from the fixation target, and after a short interval, the second saccade brings it back toward the target. SWJs are prevalent in certain neurological disorders, including progressive supranuclear palsy (PSP). Here, we developed an objective method to identify SWJs. We found that SWJs are more frequent, larger, and more markedly horizontal in PSP patients than in healthy human subjects. Furthermore, the loss of a vertical component in fixational saccades and SWJs was the eye movement feature that best distinguished PSP patients from controls. We moreover determined that, in PSP patients and controls, the larger the saccade the more likely it was part of a SWJ. Furthermore, saccades produced by PSP patients had equivalent properties whether they were part of a SWJ or not, suggesting that normal fixational saccades (microsaccades) are rare in PSP. We propose that fixational saccades and SIs are generated by the same neural circuit and that, both in PSP patients and in controls, SWJs result from a coupling mechanism that generates a second corrective saccade shortly after a large fixation saccade. Because of brainstem and/or cerebellum impairment, fixational saccades in PSP are abnormally large and thus more likely to trigger a corrective saccade, giving rise to SWJs.
Project description:Current theories discussing the role of the cerebellum have been consistently pointing towards the concept of motor learning. The unavailability of a structure for motor learning able to use information on past errors to change future movements should cause consistent metrical deviations and an inability to correct them; however, it should not boost "motor noise." However, dysmetria, a loss of endpoint precision and an increase in endpoint variability ("motor noise") of goal-directed movements is the central aspect of cerebellar ataxia. Does the prevention of dysmetria or "motor noise" by the healthy cerebellum tell us anything about its normal function? We hypothesize that the healthy cerebellum is able to prevent dysmetria by adjusting movement duration such as to compensate changes in movement velocity. To address this question, we studied fast goal-directed index finger movements in patients with global cerebellar degeneration and in healthy subjects. We demonstrate that healthy subjects are able to maintain endpoint precision despite continuous fluctuations in movement velocity because they are able to adjust the overall movement duration in a fully compensatory manner ("velocity-duration trade-off"). We furthermore provide evidence that this velocity-duration trade-off accommodated by the healthy cerebellum is based on a priori information on the future movement velocity. This ability is lost in cerebellar disease. We suggest that the dysmetria observed in cerebellar patients is a direct consequence of the loss of a cerebellum-based velocity-duration trade-off mechanism that continuously fine-tunes movement durations using information on the expected velocity of the upcoming movement.
Project description:The spinocerebellar ataxia type 2 is a neurodegenerative disease with autosomal dominant inheritance; clinically characterized by progressive cerebellar ataxia, slow ocular saccades, nystagmus, ophthalmoplegia, dysarthria, dysphagia, cognitive deterioration, mild dementia, peripheral neuropathy. Infantile onset is a rare presentation that only has been reported in four instances in the literature. In the present work a boy aged 5 years 7 months was studied due to horizontal gaze-evoked nystagmus, without saccades, ataxic gait, dysarthria, dysphagia, dysmetria, generalized spasticity mainly pelvic, bilateral Babinsky. The mother aged 27 years-old presented progressive cerebellar ataxia, dysarthria, dysmetria, dysdiadochokinesis, limb ataxia and olivopontocerebellar atrophy. The molecular analysis was made by identifying the expansion repeats in tandem by long PCR to analyze the repeats in the ATXN2 gene. We found an extreme CAG expansion repeats of ~884 repeats in the child. We describe a Mexican child affected by SCA2 with an infantile onset, associated with a high number of CAG repeats previously no reported and anticipation phenomenon.
Project description:Background: Spinocerebellar ataxia type 3 (SCA) is a cerebellum-dominant degenerative disorder that is characterized primarily by infratentorial damage, although less severe supratentorial involvement may contribute to the clinical manifestation. These impairments may result from the efferent loss of the cerebellar cortex and degeneration of the cerebral cortex. Method: We used the three-dimensional fractal dimension (3D-FD) method to quantify the morphological changes in the supratentorial regions and assessed atrophy in the relatively focal regions in patients with SCA3. A total of 48 patients with SCA3 and 50 sex- and age-matched healthy individuals, as the control group, participated in this study. The 3D-FD method was proposed to distinguish 97 automatic anatomical label regions of gray matter (left cerebrum: 45, right cerebrum: 45, cerebellum: 7) between healthy individuals and patients with SCA3. Results: Patients with SCA3 exhibited reduced brain complexity within both the traditional olivopontocerebellar atrophy (OPCA) pattern and specific supratentorial regions. The study results confirmed the extensive involvement of extracerebellar regions in SCA3. The atrophied regions of SCA3 in infratentorial and supratentorial cortex showed a wide range of overlapped areas as in two functional cortexes, namely cerebellum-related cortex and basal ganglia-related cortex. Conclusions: Our results found that the atrophy of the SCA3 are not only limited in the infratentorial regions. Both cerebellar related cortex and basal ganglia related cortex were affected in the disease process of SCA3. Our findings might correlate to the common symptoms of SCA3, such as ataxia, Parkinsonism, dysarthria, and dysmetria. SCA3 should no longer be considered a disease limited to the cerebellum and its connections; rather, it should be considered a pathology affecting the whole brain.