Dysfunctional mode switching between fixation and saccades: collaborative insights into two unusual clinical disorders.

Voluntary rapid eye movements (saccades) redirect the fovea toward objects of visual interest. The saccadic system can be considered as a dual-mode system: in one mode the eye is fixating, in the other it is making a saccade. In this review, we consider two examples of dysfunctional saccades, interrupted saccades in late-onset Tay-Sachs disease and gaze-position dependent opsoclonus after concussion, which fail to properly shift between fixation and saccade modes. Insights and benefits gained from bi-directional collaborative exchange between clinical and basic scientists are emphasized. In the case of interrupted saccades, existing mathematical models were sufficiently detailed to provide support for the cause of interrupted saccades. In the case of gaze-position dependent opsoclonus, existing models could not explain the behavior, but further development provided a reasonable hypothesis for the mechanism underlying the behavior. Collaboration between clinical and basic science is a rich source of progress for developing biologically plausible models and understanding neurological disease. Approaching a clinical problem with a specific hypothesis (model) in mind often prompts new experimental tests and provides insights into basic mechanisms.

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.

Modeling gaze position-dependent opsoclonus.

Opsoclonus/flutter (O/F) is a rare disorder of the saccadic system. Previously, we modeled O/F that developed in a patient following abuse of anabolic steroids. That model, as in all models of the saccadic system, generates commands to make a change in eye position. Recently, we saw a patient who developed a unique form of opsoclonus following a concussion. The patient had postsaccadic ocular flutter in both directions of gaze, and opsoclonus during fixation and pursuit in the left hemifield. A new model of the saccadic system is needed to account for this gaze-position dependent O/F. We started with our prior model, which contains two key elements, mutual inhibition between inhibitory burst neurons on both sides and a prolonged reactivation time of the omnipause neurons (OPNs). We included new inputs to the OPNs from the nucleus prepositus hypoglossi and the frontal eye fields, which contain position-dependent neurons. This provides a mechanism for delaying OPN reactivation, and creating a gaze-position dependence. A simplified pursuit system was also added, the output of which inhibits the OPNs, providing a mechanism for gaze-dependence during pursuit. The rest of the model continues to generate a command to change eye position.

Eye position-dependent opsoclonus in mild traumatic brain injury.

Opsoclonus consists of bursts of involuntary, multidirectional, back-to-back saccades without an intersaccadic interval. We report a 60-year-old man with post-concussive headaches and disequilibrium who had small amplitude opsoclonus in left gaze, along with larger amplitude flutter during convergence. Examination was otherwise normal and brain MRI was unremarkable. Video-oculography demonstrated opsoclonus predominantly in left gaze and during pursuit in the left hemifield, which improved as post-concussive symptoms improved. Existing theories of opsoclonus mechanisms do not account for this eye position-dependence. We discuss theoretical mechanisms of this behavior, including possible dysfunction of frontal eye field and/or cerebellar vermis neurons; review ocular oscillations in traumatic brain injury; and consider the potential relationship between the larger amplitude flutter upon convergence and post-traumatic ocular oscillations.

Motion and binocular disparity processing: Two sides of two different coins.

From a mathematical point of view, extracting motion and disparity signals from a binocular visual stream requires very similar operations, applied over time for motion and across eyes for disparity. This similarity is reflected in the theories that have been proposed to describe the neural mechanisms used by the brain to extract these signals. At the behavioral level there are, however, several differences in how humans react to these stimuli, which presumably reflect differences in how these signals are processed by the brain. Here we highlight three such differences: the degree to which different axes of motion/disparity are treated isotropically, the importance of reference signals, and the rules that underlie the combination of 1D signals to extract 2D signals.

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.

Binocular Summation for Reflexive Eye Movements: A Potential Diagnostic Tool for Stereodeficiencies.

Purpose: Stereoscopic vision, by detecting interocular correlations, enhances depth perception. Stereodeficiencies often emerge during the first months of life, and left untreated can lead to severe loss of visual acuity in one eye and/or strabismus. Early treatment results in much better outcomes, yet diagnostic tests for infants are cumbersome and not widely available. We asked whether reflexive eye movements, which in principle can be recorded even in infants, can be used to identify stereodeficiencies. Methods: Reflexive ocular following eye movements induced by fast drifting noise stimuli were recorded in 10 adult human participants (5 with normal stereoacuity, 5 stereodeficient). To manipulate interocular correlation, the stimuli shown to the two eyes were either identical, different, or had opposite contrast. Monocular presentations were also interleaved. The participants were asked to passively fixate the screen. Results: In the participants with normal stereoacuity, the responses to binocular identical stimuli were significantly larger than those induced by binocular opposite stimuli. In the stereodeficient participants the responses were indistinguishable. Despite the small size of ocular following responses, 40 trials, corresponding to less than 2 minutes of testing, were sufficient to reliably differentiate normal from stereodeficient participants. Conclusions: Ocular-following eye movements, because of their reliance on cortical neurons sensitive to interocular correlations, are affected by stereodeficiencies. Because these eye movements can be recorded noninvasively and with minimal participant cooperation, they can potentially be measured even in infants and might thus provide an useful screening tool for this currently underserved population.

Modeling the Triggering of Saccades, Microsaccades, and Saccadic Intrusions.

When we explore a static visual scene, our eyes move in a sequence of fast eye movements called saccades, which are separated by fixation periods of relative eye stability. Based on uncertain sensory and cognitive inputs, the oculomotor system must decide, at every moment, whether to initiate a saccade or to remain in the fixation state. Even when we attempt to maintain our gaze on a small spot, small saccades, called microsaccades, intrude on fixation once or twice per second. Because microsaccades occur at the boundary of the decision to maintain fixation versus starting a saccade, they offer a unique opportunity to study the mechanisms that control saccadic triggering. Abnormal saccadic intrusions can occur during attempted fixation in patients with neurodegenerative disorders. We have implemented a model of the triggering mechanism of saccades, based on known anatomy and physiology, that successfully simulates the generation of saccades of any size-including microsaccades in healthy observers, and the saccadic intrusions that interrupt attempted fixation in parkinsonian patients. The model suggests that noisy neuronal activity in the superior colliculus controls the state of a mutually inhibitory network in the brain stem formed by burst neurons and omnipause neurons. When the neuronal activity is centered at the rostral pole, the system remains at a state of fixation. When activity is perturbed away from this center, a saccade is triggered. This perturbation can be produced either by the intent to move one's gaze or by random fluctuations in activity.

Binocular summation for reflexive eye movements.

Psychophysical studies and our own subjective experience suggest that, in natural viewing conditions (i.e., at medium to high contrasts), monocularly and binocularly viewed scenes appear very similar, with the exception of the improved depth perception provided by stereopsis. This phenomenon is usually described as a lack of binocular summation. We show here that there is an exception to this rule: Ocular following eye movements induced by the sudden motion of a large stimulus, which we recorded from three human subjects, are much larger when both eyes see the moving stimulus, than when only one eye does. We further discovered that this binocular advantage is a function of the interocular correlation between the two monocular images: It is maximal when they are identical, and reduced when the two eyes are presented with different images. This is possible only if the neurons that underlie ocular following are sensitive to binocular disparity.

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.

Suppression and Contrast Normalization in Motion Processing.

Sensory neurons are activated by a range of stimuli to which they are said to be tuned. Usually, they are also suppressed by another set of stimuli that have little effect when presented in isolation. The interactions between preferred and suppressive stimuli are often quite complex and vary across neurons, even within a single area, making it difficult to infer their collective effect on behavioral responses mediated by activity across populations of neurons. Here, we investigated this issue by measuring, in human subjects (three males), the suppressive effect of static masks on the ocular following responses induced by moving stimuli. We found a wide range of effects, which depend in a nonlinear and nonseparable manner on the spatial frequency, contrast, and spatial location of both stimulus and mask. Under some conditions, the presence of the mask can be seen as scaling the contrast of the driving stimulus. Under other conditions, the effect is more complex, involving also a direct scaling of the behavioral response. All of this complexity at the behavioral level can be captured by a simple model in which stimulus and mask interact nonlinearly at two stages, one monocular and one binocular. The nature of the interactions is compatible with those observed at the level of single neurons in primates, usually broadly described as divisive normalization, without having to invoke any scaling mechanism.SIGNIFICANCE STATEMENT The response of sensory neurons to their preferred stimulus is often modulated by stimuli that are not effective when presented alone. Individual neurons can exhibit multiple modulatory effects, with considerable variability across neurons even in a single area. Such diversity has made it difficult to infer the impact of these modulatory mechanisms on behavioral responses. Here, we report the effects of a stationary mask on the reflexive eye movements induced by a moving stimulus. A model with two stages, each incorporating a divisive modulatory mechanism, reproduces our experimental results and suggests that qualitative variability of masking effects in cortical neurons might arise from differences in the extent to which such effects are inherited from earlier stages.

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'.

Combining 1-D components to extract pattern information: It is about more than component similarity.

At least under some conditions, plaid stimuli are processed by combining information first extracted in orientation and scale-selective channels. The rules that govern this combination across channels are only partially understood. Although the available data suggests that only components having similar spatial frequency and contrast are combined, the extent to which this holds has not been firmly established. To address this question, we measured, in human subjects, the short-latency reflexive vergence eye movements induced by stereo plaids in which spatial frequency and contrast of the components are independently varied. We found that, although similarity in component spatial frequency and contrast matter, they interact in a nonseparable way. One way in which this relationship might arise is if the internal estimate of contrast is not a faithful representation of stimulus contrast but is instead spatial frequency-dependent (with higher spatial frequencies being boosted). We propose that such weighting might have been put in place by a mechanism that, in an effort of achieve contrast constancy and/or coding efficiency, regulates the gain of detectors in early visual cortex to equalize their long-term average response to natural images.

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.

Impaired Motor Learning in a Disorder of the Inferior Olive: Is the Cerebellum Confused?

An attractive hypothesis about how the brain learns to keep its motor commands accurate is centered on the idea that the cerebellar cortex associates error signals carried by climbing fibers with simultaneous activity in parallel fibers. Motor learning can be impaired if the error signals are not transmitted, are incorrect, or are misinterpreted by the cerebellar cortex. Learning might also be impaired if the brain is overwhelmed with a sustained barrage of meaningless information unrelated to simultaneously appearing error signals about incorrect performance. We test this concept in subjects with syndrome of oculopalatal tremor (OPT), a rare disease with spontaneous, irregular, roughly pendular oscillations of the eyes thought to reflect an abnormal, synchronous, spontaneous discharge to the cerebellum from the degenerating neurons in the inferior olive. We examined motor learning during a short-term, saccade adaptation paradigm in patients with OPT and found a unique pattern of disturbed adaptation, quite different from the abnormal adaption when the cerebellum is involved directly. Both fast (seconds) and slow (minutes) timescales of learning were impaired. We suggest that the spontaneous, continuous, synchronous output from the inferior olive prevents the cerebellum from receiving the error signals it needs for appropriate motor learning. The important message from this study is that impaired motor adaptation and resultant dysmetria is not the exclusive feature of cerebellar disorders, but it also highlights disorders of the inferior olive and its connections to the cerebellum.

A Motion-from-Form Mechanism Contributes to Extracting Pattern Motion from Plaids.

Since the discovery of neurons selective for pattern motion direction in primate middle temporal area MT (Albright, 1984; Movshon et al., 1985), the neural computation of this signal has been the subject of intense study. The bulk of this work has explored responses to plaids obtained by summing two drifting sinusoidal gratings. Unfortunately, with these stimuli, many different mechanisms are similarly effective at extracting pattern motion. We devised a new set of stimuli, obtained by summing two random line stimuli with different orientations. This allowed several novel manipulations, including generating plaids that do not contain rigid 2D motion. Importantly, these stimuli do not engage most of the previously proposed mechanisms. We then recorded the ocular following responses that such stimuli induce in human subjects. We found that pattern motion is computed even with stimuli that do not cohere perceptually, including those without rigid motion, and even when the two gratings are presented separately to the two eyes. Moderate temporal and/or spatial separation of the gratings impairs the computation. We show that, of the models proposed so far, only those based on the intersection-of-constraints rule, embedding a motion-from-form mechanism (in which orientation signals are used in the computation of motion direction signals), can account for our results. At least for the eye movements reported here, a motion-from-form mechanism is thus involved in one of the most basic functions of the visual motion system: extracting motion direction from complex scenes. SIGNIFICANCE STATEMENT: Anatomical considerations led to the proposal that visual function is organized in separate processing streams: one (ventral) devoted to form and one (dorsal) devoted to motion. Several experimental results have challenged this view, arguing in favor of a more integrated view of visual processing. Here we add to this body of work, supporting a role for form information even in a function--extracting pattern motion direction from complex scenes--for which decisive evidence for the involvement of form signals has been lacking.

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.