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.

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.

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 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.

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.

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.

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.

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'.

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.

Coffin-Siris and Nicolaides-Baraitser syndromes are a common well recognizable cause of intellectual disability.

BACKGROUND: Nicolaides-Baraitser and Coffin-Siris syndromes are emerging conditions with overlapping clinical features including intellectual disability and typical somatic characteristics, especially sparse hair, low frontal hairline, large mouth with thick and everted lips, and hands and feet anomalies. Since 2012, mutations in genes encoding six proteins of the BAF complex were identified in both conditions. METHODS AND RESULTS: We have clinically evaluated a cohort of 1161 patients with intellectual disability from three different Italian centers. A strong clinical suspicion of either Nicolaides-Baraitser syndrome or Coffin-Siris syndrome was proposed in 11 cases who were then molecularly confirmed: 8 having de novo missense mutations in SMARCA2, two frame-shift mutations in ARID1B and one missense mutation in SMARCB1. Given the high frequency of the condition we set up a one-step deep sequencing test for all 6 genes of the BAF complex. CONCLUSIONS: These results prove that the frequency of these conditions may be as high as the most common syndromes with intellectual deficit (about 1%). Clinical geneticists should be well aware of this group of disorders in the clinical setting when ascertaining patients with intellectual deficit, the specific facial features being the major diagnostic handle. Finally, this work adds information on the clinical differences of the two conditions and presents a fast and sensitive test for the molecular diagnosis.

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.

Ocular-motor profile and effects of memantine in a familial form of adult cerebellar ataxia with slow saccades and square wave saccadic intrusions.

Fixation instability due to saccadic intrusions is a feature of autosomal recessive spinocerebellar ataxias, and includes square wave intrusions (SWI) and macrosaccadic oscillations (MSO). A recent report suggested that the non-competitive antagonist of NMDA receptors, memantine, could decrease MSO and improve fixation in patients with spinocerebellar ataxia with saccadic intrusions (SCASI). We similarly tested two sisters, respectively of 58 and 60 years, with an unrecognized form of recessive, adult-onset cerebellar ataxia, peripheral neuropathy and slow saccades, who showed prominent SWI and also complained with difficulty in reading. We tested horizontal visually guided saccades (10°-18°) and three minutes of steady fixation in each patient and in thirty healthy controls. Both patients showed a significant reduction of peak and mean velocity compared with control subjects. Large SWI interrupting steady fixation were prominent during steady fixation and especially following visually guided saccades. Eye movements were recorded before and during the treatment with memantine, 20 mg/daily for 6 months. The treatment with memantine reduced both the magnitude and frequency of SWI (the former significantly), but did not modified neurological conditions or saccade parameters. Thus, our report suggests that memantine may have some general suppressive effect on saccadic intrusions, including both SWI and MSO, thereby restoring the capacity of reading and visual attention in these and in other recessive forms of ataxia, including Friedreich's, in which saccadic intrusions are prominent.