Different saccadic profile in bulbar versus spinal-onset amyotrophic lateral sclerosis.

Two clinical phenotypes characterize the onset of amyotrophic lateral sclerosis (ALS): the spinal variant, with symptoms beginning in the limbs, and the bulbar variant, affecting firstly speech and swallowing. The two variants show some distinct features in the histopathology, localization and prognosis, but to which extent they really differ clinically and pathologically remains to be clarified. Recent neuropathological and neuroimaging studies have suggested a broader spreading of the neurodegenerative process in ALS, extending beyond the motor areas, toward other cortical and deep grey matter regions, many of which are involved in visual processing and saccadic control. Indeed, a wide range of eye movement deficits have been reported in ALS, but they have never been used to distinguish the two ALS variants. Since quantifying eye movements is a very sensitive and specific method for the study of brain networks, we compared different saccadic and visual search behaviours across spinal ALS patients (n = 12), bulbar ALS patients (n = 6) and healthy control subjects (n = 13), along with cognitive and MRI measures, with the aim to define more accurately the two patients subgroups and possibly clarify a different underlying neural impairment. We found separate profiles of visually-guided saccades between spinal (short saccades) and bulbar (slow saccades) ALS, which could result from the pathologic involvement of different pathways. We suggest an early involvement of the parieto-collicular-cerebellar network in spinal ALS and the fronto-brainstem circuit in bulbar ALS. Overall, our data confirm the diagnostic value of the eye movements analysis in ALS and add new insight on the involved neural networks.

Eye movement changes in autosomal dominant spinocerebellar ataxias.

Oculomotor abnormalities are common findings in spinocerebellar ataxias (SCAs), a clinically heterogeneous group of neurodegenerative disorders with an autosomal dominant pattern of inheritance. Usually, cerebellar impairment accounts for most of the eye movement changes encountered; as the disease progresses, the involvement of extracerebellar structures typically seen in later stages may modify the oculomotor progression. However, ocular movement changes are rarely specific. In this regard, some important exceptions include the prominent slowing of horizontal eye movements in SCA2 and, to a lesser extent, in SCA3, SCA4, and SCA28, or the executive deficit in SCA2 and SCA17. Here, we report the eye movement abnormalities and neurological pictures of SCAs through a review of the literature. Genetic and neuropathological/neuroimaging aspects are also briefly discussed. Overall, the findings reported indicate that oculomotor analysis could be of help in differential diagnosis among SCAs and contribute to clarify the role of brain structures, particularly the cerebellum, in oculomotor control.

Evidence From Parkinson's Disease That the Superior Colliculus Couples Action and Perception.

BACKGROUND: Action and perception should be coordinated for good visual-motor performance. The mechanism coupling action and perception may be a prominence map in the intermediate layer of the superior colliculus that modulates motor and attentional/perceptual processes. This coordination comes with a cost: the misperception that briefly overlapping stimuli are separated in time. Our model predicts that abnormal intermediate layer of the superior colliculus inhibition, such as that arising from increased basal ganglia output, would affect the action and perception coupling, and it would worsen the misperception. OBJECTIVE: To test the prominence map model by measuring reaction times and perceptions in human intermediate layer of the superior colliculus dysfunction. METHODS: We measured the saccadic and perceptual reaction time changes and the percept for different temporal asynchronies between fixation point offset and peripheral target onset in Parkinson's disease (PD). RESULTS: We found that increased basal ganglia inhibitory output to the intermediate layer of the superior colliculus prominence map disrupted the normal coupling of action and perception. With increasing temporal asynchronies, the PD perceptual reaction times increased approximately 3 times more than the increase of the saccadic reaction times. Also, PD subjects misperceive small overlaps as gaps for temporal asynchronies up to 3 times longer than controls. The results can be reproduced by an intermediate layer of the superior colliculus rostral-caudal gradient of inhibition. CONCLUSION: These findings support the hypothesis that a prominence map in the intermediate layer of the superior colliculus couples action and perception through modulation of attention. A dysfunction of this network quantifies abnormal basal ganglia output and could underlie visual deficits, including common, yet poorly understood, misperceptions and visual-motor deficits of PD. © 2019 International Parkinson and Movement Disorder Society.

The role of dentate nuclei in human oculomotor control: insights from cerebrotendinous xanthomatosis.

KEY POINTS: A cerebellar dentate nuclei (DN) contribution to volitional oculomotor control has recently been hypothesized but not fully understood. Cerebrotendinous xanthomatosis (CTX) is a rare neurometabolic disease typically characterized by DN damage. In this study, we compared the ocular movement characteristics of two sets of CTX patients, with and without brain MRI evidence of DN involvement, with a set of healthy subjects. Our results suggest that DN participate in voluntary behaviour, such as the execution of antisaccades, and moreover are involved in controlling the precision of the ocular movement. The saccadic abnormalities related to DN involvement were independent of global and regional brain atrophy. Our study confirms the relevant role of DN in voluntary aspects of oculomotion and delineates specific saccadic abnormalities that could be used to detect the involvement of DN in other cerebellar disorders. ABSTRACT: It is well known that the medial cerebellum controls saccadic speed and accuracy. In contrast, the role of the lateral cerebellum (cerebellar hemispheres and dentate nuclei, DN) is less well understood. Cerebrotendinous xanthomatosis (CTX) is a lipid storage disorder due to mutations in CYP27A1, typically characterized by DN damage. CTX thus provides a unique opportunity to study DN in human oculomotor control. We analysed horizontal and vertical visually guided saccades and horizontal antisaccades of 19 CTX patients. Results were related to the presence/absence of DN involvement and compared with those of healthy subjects. To evaluate the contribution of other areas, abnormal saccadic parameters were compared with global and regional brain volumes. CTX patients executed normally accurate saccades with normal main sequence relationships, indicating that the brainstem and medial cerebellar structures were functionally spared. Patients with CTX executed more frequent multistep saccades and directional errors during the antisaccade task than controls. CTX patients with DN damage showed less precise saccades with longer latencies, and more frequent directional errors, usually not followed by corrections, than either controls or patients without DN involvement. These saccadic abnormalities related to DN involvement but were independent of global and regional brain atrophy. We hypothesize that two different cerebellar networks contribute to the metrics of a movement: the medial cerebellar structures determine accuracy, whereas the lateral cerebellar structures control precision. The lateral cerebellum (hemispheres and DN) also participates in modulating goal directed gaze behaviour, by prioritizing volitional over reflexive movements.

Action and perception are temporally coupled by a common mechanism that leads to a timing misperception.

We move our eyes to explore the world, but visual areas determining where to look next (action) are different from those determining what we are seeing (perception). Whether, or how, action and perception are temporally coordinated is not known. The preparation time course of an action (e.g., a saccade) has been widely studied with the gap/overlap paradigm with temporal asynchronies (TA) between peripheral target onset and fixation point offset (gap, synchronous, or overlap). However, whether the subjects perceive the gap or overlap, and when they perceive it, has not been studied. We adapted the gap/overlap paradigm to study the temporal coupling of action and perception. Human subjects made saccades to targets with different TAs with respect to fixation point offset and reported whether they perceived the stimuli as separated by a gap or overlapped in time. Both saccadic and perceptual report reaction times changed in the same way as a function of TA. The TA dependencies of the time change for action and perception were very similar, suggesting a common neural substrate. Unexpectedly, in the perceptual task, subjects misperceived lights overlapping by less than ∼100 ms as separated in time (overlap seen as gap). We present an attention-perception model with a map of prominence in the superior colliculus that modulates the stimulus signal's effectiveness in the action and perception pathways. This common source of modulation determines how competition between stimuli is resolved, causes the TA dependence of action and perception to be the same, and causes the misperception.

Spatial ranking strategy and enhanced peripheral vision discrimination optimize performance and efficiency of visual sequential search.

Visual sequential search might use a peripheral spatial ranking of the scene to put the next target of the sequence in the correct order. This strategy, indeed, might enhance the discriminative capacity of the human peripheral vision and spare neural resources associated with foveation. However, it is not known how exactly the peripheral vision sustains sequential search and whether the sparing of neural resources has a cost in terms of performance. To elucidate these issues, we compared strategy and performance during an alpha-numeric sequential task where peripheral vision was modulated in three different conditions: normal, blurred, or obscured. If spatial ranking is applied to increase the peripheral discrimination, its use as a strategy in visual sequencing should differ according to the degree of discriminative information that can be obtained from the periphery. Moreover, if this strategy spares neural resources without impairing the performance, its use should be associated with better performance. We found that spatial ranking was applied when peripheral vision was fully available, reducing the number and time of explorative fixations. When the periphery was obscured, explorative fixations were numerous and sparse; when the periphery was blurred, explorative fixations were longer and often located close to the items. Performance was significantly improved by this strategy. Our results demonstrated that spatial ranking is an efficient strategy adopted by the brain in visual sequencing to highlight peripheral detection and discrimination; it reduces the neural cost by avoiding unnecessary foveations, and promotes sequential search by facilitating the onset of a new saccade.

Eight and a half syndrome with hemiparesis and hemihypesthesia: the nine syndrome?

"Eight-and-a-half" syndrome is "one-and-a-half" syndrome (conjugated horizontal gaze palsy and internuclear ophthalmoplegia) plus ipsilateral fascicular cranial nerve seventh palsy. This rare condition, particularly when isolated, is caused by circumscribed lesions of the pontine tegmentum involving the abducens nucleus, the ipsilateral medial longitudinal fasciculus, and the adjacent facial colliculus. Its recognition is therefore of considerable diagnostic value. We report a 71-year-old man who presented with eight and a half syndrome associated with contralateral hemiparesis and hemihypesthesia, in which brain magnetic resonance imaging scans revealed a lacunar pontine infarction also involving the corticospinal tract and medial lemniscus. These features could widen the spectrum of pontine infarctions, configuring a possible "nine" syndrome.

Visual system involvement in CADASIL.

BACKGROUND AND OBJECTIVE: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary arteriolar small-vessel disease caused by Notch3 mutations. A detailed definition of the neuro-ophthalmologic spectrum of CADASIL might provide new insights in the pathophysiology of small-vessel diseases. Therefore, this study aims to precisely delineate the features and the prevalence of the visual system impairment in CADASIL. METHODS: A cohort of 34 genetically confirmed CADASIL patients was enrolled in an observational cross-sectional study. Subjects underwent a complete neuro-ophthalmological evaluation. Clinical features and common cardiovascular risk factors were also considered. Data were compared with those already reported in previous studies. RESULTS: Both afferent and efferent visual structures were commonly impaired in CADASIL patients. Retinal microvascular changes such as arteriolar narrowing and arteriovenous nicking, described in most patients and detected also in asymptomatic carriers, reflect the typical hemodynamic changes of CADASIL. However, less frequent findings, like early macular and lens changes, would indicate a possible further role played by susceptibility to premature aging and degeneration. Cotton wool spots and vessel occlusions were not common. Finally, eye movement abnormalities suggest that the brainstem is particularly vulnerable to damage in CADASIL. CONCLUSIONS: Although no specific or prominent neuro-ophthalmologic finding can be considered as hallmark of the disease, afferent and efferent visual system abnormalities could be accounted as complementary markers to study cerebral small-vessel diseases.

Autosomal recessive cerebellar ataxias: a diagnostic classification approach according to ocular features.

Autosomal recessive cerebellar ataxias (ARCAs) are a heterogeneous group of neurodegenerative disorders affecting primarily the cerebellum and/or its afferent tracts, often accompanied by damage of other neurological or extra-neurological systems. Due to the overlap of clinical presentation among ARCAs and the variety of hereditary, acquired, and reversible etiologies that can determine cerebellar dysfunction, the differential diagnosis is challenging, but also urgent considering the ongoing development of promising target therapies. The examination of afferent and efferent visual system may provide neurophysiological and structural information related to cerebellar dysfunction and neurodegeneration thus allowing a possible diagnostic classification approach according to ocular features. While optic coherence tomography (OCT) is applied for the parametrization of the optic nerve and macular area, the eye movements analysis relies on a wide range of eye-tracker devices and the application of machine-learning techniques. We discuss the results of clinical and eye-tracking oculomotor examination, the OCT findings and some advancing of computer science in ARCAs thus providing evidence sustaining the identification of robust eye parameters as possible markers of ARCAs.

Differences in saccade dynamics between spinocerebellar ataxia 2 and late-onset cerebellar ataxias.

The cerebellum is implicated in maintaining the saccadic subsystem efficient for vision by minimizing movement inaccuracy and by learning from endpoint errors. This ability is often disrupted in degenerative cerebellar diseases, as demonstrated by saccade kinetic abnormalities. The study of saccades in these patients may therefore provide insights into the neural substrate underlying saccadic motor control. We investigated the different extent of saccade dynamic abnormalities in spinocerebellar ataxia type 2 and late-onset cerebellar ataxias, genetically undefined and with prevalent cerebellar atrophy. Reflexive and voluntary saccades of different amplitude (10°-18°) were studied in seven patients with spinocerebellar ataxia 2, eight patients with late-onset cerebellar ataxia and 25 healthy controls. Quantitative analysis of saccade parameters and measures of saccade accuracy were performed. Detailed neurological, neurophysiological and magnetic resonance imaging assessment was obtained for each patient. Genetic and laboratory screening for spinocerebellar ataxias and other forms of late-onset cerebellar ataxias were also performed. A lower peak saccade velocity and longer duration was observed in patients with spinocerebellar ataxia 2 with respect to those with late-onset cerebellar ataxia and controls. Unlike subjects with spinocerebellar ataxia 2, patients with late-onset cerebellar ataxia showed main sequence relationships to similar saccades made by normal subjects. Saccades were significantly more inaccurate, namely hypometric, in late-onset cerebellar ataxia than in spinocerebellar ataxia 2 and inaccuracy increased with saccade amplitude. The percentage of hypometric primary saccades and of larger secondary corrective saccades were consistently higher in late-onset cerebellar ataxia than in spinocerebellar ataxia 2 and controls. No other significant differences were found between groups. Two different mechanisms were adopted to redirect the fovea as fast and/or accurately as possible to peripheral targets by the two groups of cerebellar patients. Patients with spinocerebellar ataxia 2 maintained accuracy using slow saccades with longer duration. This reflects prevalent degenerative processes affecting the pontine burst generator and leading to saccade velocity failure. On the other hand, patients with late-onset cerebellar ataxia reached the target with a number of fast inaccurate, mostly hypometric saccades. Different degrees of cerebellar oculomotor vermis involvement may account for differences in optimizing the trade-off between velocity and accuracy in the two groups. In addition, as suggested by spinocerebellar patients having slow saccades that are no longer ballistic, visual feedback might be continuously available during the movement execution to guide the eye to its target.

Retinal nerve fiber layer thinning in CADASIL: an optical coherence tomography and MRI study.

BACKGROUND AND PURPOSE: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is considered a genetic form of small-vessel disease causing subcortical dementia. A relevant role of axonal injury was recently proposed to explain disability and cognitive decline in this disease. The retinal nerve fiber layer (RNFL) is the only part of the brain where unmyelinated axons can be visualized and quantified in vivo. Their assessment may be an easily reproducible marker of neurodegenerative processes. The aim of this study was to investigate axonal degeneration in CADASIL by measuring RNFL thickness and correlating it with MRI measures of global and regional cerebral atrophy. METHODS: RNFL thickness was measured using optical coherence tomography in 17 CADASIL patients. Average values per quadrant (temporal, superior, nasal, inferior) and overall values were compared with those of normal sex- and age-matched subjects. Data of 13 patients were analyzed for correlations with MRI-based global and regional brain volumes normalized for head size. RESULTS: RNFL thickness was significantly reduced in CADASIL patients with respect to controls (p < 0.05). No significant correlations were found between RNFL thinning and brain atrophy. CONCLUSIONS: RNFL thinning suggests that retinal axonal loss occurs in CADASIL, even in the absence of subjective visual deficit.

Mathematical models and human disease.

Mathematical models of brain function are built from data covering anatomy, physiology, biophysics and behavior. In almost all cases, many possible models could fit the available data. Theoreticians make assumptions that allow them to constrain the number of possible model structures. However, a model that was more useful clinically would result if the constraints came from lesion studies in animals or clinical disorders. Here, we show a few examples of how clinical disorders have led to improvements in models. We also show a few examples of how models could lead to neural prostheses for patients. The best outcomes result when clinicians, basic scientists and theoreticians work together to understand brain function.

The cerebellum improves the precision of antisaccades by a latency-duration trade-off.

The cerebellum adapts motor responses by controlling the gain of a movement, preserving its accuracy and by learning from endpoint errors. Adaptive behavior likely acts not only in the motor but also in the sensory, behavioral, and cognitive domains, thus supporting a role of cerebellum in monitoring complex brain performances. Here, we analyzed the relationship between saccade latency, duration and endpoint error of antisaccades in a group of 10 idiopathic cerebellar atrophy (ICA) patients compared to controls. The latency distribution was decomposed in a decision time and a residual time. Both groups showed a trade-off between duration and decision time, with a peak of entropy within the range of this trade-off where the information flow was maximized. In cerebellar patients, greater reductions of duration as the time of decision increased, were associated with a lower probability for a saccade to fall near the target, with a constant low entropy outside the optimal time window. We suggest a modulation of saccade duration, depending on the latency-related decision time (accumulation of sensory and motor evidences in favor of a goal-directed movement), normally adopted to perform efficient trajectories in goal-directed saccades. This process is impaired in cerebellar patients suggesting a role for the cerebellum in monitoring voluntary motor performance by controlling the movement onset until the ambiguity of planning is resolved.

Anti-Saccades in Cerebellar Ataxias Reveal a Contribution of the Cerebellum in Executive Functions.

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.

A GABAergic Dysfunction in the Olivary-Cerebellar-Brainstem Network May Cause Eye Oscillations and Body Tremor. II. Model Simulations of Saccadic Eye Oscillations.

Eye and body oscillations are shared features of several neurological diseases, yet their pathophysiology remains unclear. Recently, we published a report on two tennis players with a novel presentation of eye and body oscillations following self-administration of performance-enhancing substances. Opsoclonus/flutter and limb tremor were diagnosed in both patients. Common causes of opsoclonus/flutter were excluded. High-resolution eye movement recordings from one patient showed novel spindle-shaped, asymmetric saccadic oscillations (at ~3.6 Hz) and ocular tremor (~40-60 Hz). Based on these findings, we proposed that the oscillations are the result of increased GABAA receptor sensitivity in a circuit involving the cerebellum (vermis and fastigial nuclei), the inferior olives, and the brainstem saccade premotor neurons (excitatory and inhibitory burst neurons, and omnipause neurons). We present a mathematical model of the saccadic system, showing that the proposed dysfunction in the network can reproduce the types of saccadic oscillations seen in these patients.

What stops a saccade?

Rapid movements to a target are ballistic; they usually do not last long enough for visual feedback about errors to influence them. Yet, the brain is not simply precomputing movement trajectory. Classical models of movement control involve a feedback loop that subtracts 'where we are now' from 'where we want to be'. That difference is an internal motor error. The feedback loop reduces this error until it reaches zero, stopping the movement. However, neurophysiological studies have shown that movements controlled by the cerebrum (e.g. arm and head movements) and those controlled by the brain stem (e.g. tongue and eye movements) are also controlled, in parallel, by the cerebellum. Thus, there may not be a single error control loop. We propose an alternative to feedback error control, wherein the cerebellum uses adaptive, velocity feedback, integral control to stop the movement on target.This article is part of the themed issue 'Movement suppression: brain mechanisms for stopping and stillness'.

Eye Movements in Parkinson's Disease and Inherited Parkinsonian Syndromes.

Despite extensive research, the functions of the basal ganglia (BG) in movement control have not been fully understood. Eye movements, particularly saccades, are convenient indicators of BG function. Here, we review the main oculomotor findings reported in Parkinson's disease (PD) and genetic parkinsonian syndromes. PD is a progressive, neurodegenerative disorder caused by dopaminergic cell loss within the substantia nigra pars compacta, resulting in depletion of striatal dopamine and subsequent increased inhibitory BG output from the internal globus pallidus and the substantia nigra pars reticulata. Eye movement abnormalities are common in PD: anomalies are more evident in voluntary than reflexive saccades in the initial stages, but visually guided saccades may also be involved at later stages. Saccadic hypometria (including abnormally fragmented saccades), reduced accuracy, and increased latency are among the most prominent deficits. PD patients show also unusually frequent and large square wave jerks and impaired inhibition of reflexive saccades when voluntary mirror saccades are required. Poor convergence ability and altered pursuit are common. Inherited parkinsonisms are a heterogeneous group of rare syndromes due to gene mutations causing symptoms resembling those of PD. Eye movement characteristics of some parkinsonisms have been studied. While sharing some PD features, each syndrome has a distinctive profile that could contribute to better define the clinical phenotype of parkinsonian disorders. Moreover, because the pathogenesis and the underlying neural circuit failure of inherited parkinsonisms are often well defined, they might offer a better prospect than idiopathic PD to understand the BG function.

Characteristic Eye Movements in Ataxia-Telangiectasia-Like Disorder: An Explanatory Hypothesis.

OBJECTIVE: To investigate cerebellar dysfunctions and quantitatively characterize specific oculomotor changes in ataxia-telangiectasia-like disorder (ATLD), a rare autosomal recessive disease caused by mutations in the MRE11 gene. Additionally, to further elucidate the pathophysiology of cerebellar damage in the ataxia-telangiectasia (AT) spectrum disorders. METHODS: Saccade dynamics, metrics, and visual fixation deficits were investigated in two Italian adult siblings with genetically confirmed ATLD. Visually guided saccades were compared with those of 40 healthy subjects. Steady fixation was tested in primary and eccentric positions. Quantitative characterization of saccade parameters, saccadic intrusions (SI), and nystagmus was performed. RESULTS: Patients showed abnormally hypermetric and fast horizontal saccades to the left and greater inaccuracy than healthy subjects in all saccadic eye movements. Eye movement abnormalities included slow eye movements that preceded the initial saccade. Horizontal and vertical spontaneous jerk nystagmus, gaze-evoked, and rebound nystagmus were evident. Fixation was interrupted by large square-wave jerk SI and macrosaccadic oscillations. CONCLUSION: Slow eye movements accompanying saccades, SI, and cerebellar nystagmus are frequently seen in AT patients, additionally our ATLD patients showed the presence of fast and hypermetric saccades suggesting damage of granule cell-parallel fiber-Purkinje cell synapses of the cerebellar vermis. A dual pathogenetic mechanism involving neurodevelopmental and neurodegenerative changes is hypothesized to explain the peculiar phenotype of this disease.