Pharmacological treatment effects on eye movement control

The increasing use of eye movement paradigms to assess the functional integrity of brain systems involved in sensorimotor and cognitive processing in clinical disorders requires greater attention to effects of pharmacological treatments on these systems. This is needed to better differentiate disease and medication effects in clinical samples, to learn about neurochemical systems relevant for identified disturbances, and to facilitate identification of oculomotor biomarkers of pharmacological effects. In this review, studies of pharmacologic treatment effects on eye movements in healthy individuals are summarized and the sensitivity of eye movements to a variety of pharmacological manipulations is established. Primary findings from these studies of healthy individuals involving mainly acute effects indicate that: (i) the most consistent finding across several classes of drugs, including benzodiazepines, first- and second- generation antipsychotics, anticholinergic agents, and anticonvulsant/mood stabilizing medications is a decrease in saccade and smooth pursuit velocity (or increase in saccades during pursuit); (ii) these oculomotor effects largely reflect the general sedating effects of these medications on central nervous system functioning and are often dose-dependent; (iii) in many cases changes in oculomotor functioning are more sensitive indicators of pharmacological effects than other measures; and (iv) other agents, including the antidepressant class of serotonergic reuptake inhibitors, direct serotonergic agonists, and stimulants including amphetamine and nicotine, do not appear to adversely impact oculomotor functions in healthy individuals and may well enhance aspects of saccade and pursuit performance. Pharmacological treatment effects on eye movements across several clinical disorders including schizophrenia, affective disorders, attention deficit hyperactivity disorder, Parkinson’s disease, and Huntington’s disease are also reviewed. While greater recognition and investigation into pharmacological treatment effects in these disorders is needed, both beneficial and adverse drug effects are identified. This raises the important caveat for oculomotor studies of neuropsychiatric disorders that performance differences from healthy individuals cannot be attributed to illness effects alone. In final sections of this review, studies are presented that illustrate the utility of eye movements for use as potential biomarkers in pharmacodynamic and pharmacogenetic studies. While more systematic studies are needed, we conclude that eye movement measurements hold significant promise as tools to investigate treatment effects on cognitive and sensorimotor processes in clinical populations and that their use may be helpful in speeding the drug development pathway for drugs targeting specific neural systems and in individualizing pharmacological treatments.     

Development of eye-movement control

Cognitive control of behavior continues to improve through adolescence in parallel with important brain maturational processes including synaptic pruning and myelination, which allow for efficient neuronal computations and the functional integration of widely distributed circuitries supporting top-down control of behavior. This is also a time when psychiatric disorders, such as schizophrenia and mood disorders, emerge reflecting a particularly vulnerability to impairments in development during adolescence. Oculomotor studies provide a unique neuroscientific approach to make precise associations between cognitive control and brain circuitry during development that can inform us of impaired systems in psychopathology. In this review, we first describe the development of pursuit, fixation, and visually-guided saccadic eye movements, which collectively indicate early maturation of basic sensorimotor processes supporting reflexive, exogenously-driven eye movements. We then describe the literature on the development of the cognitive control of eye movements as reflected in the ability to inhibit a prepotent eye movement in the antisaccade task, as well as making an eye movement guided by on-line spatial information in working memory in the oculomotor delayed response task. Results indicate that the ability to make eye movements in a voluntary fashion driven by endogenous plans shows a protracted development into adolescence. Characterizing the transition through adolescence to adult-level cognitive control of behavior can inform models aimed at understanding the neurodevelopmental basis of psychiatric disorders.     

Neurophysiology and neuroanatomy of smooth pursuit in humans

Smooth pursuit eye movements enable us to focus our eyes on moving objects by utilizing well-established mechanisms of visual motion processing, sensorimotor transformation and cognition. Novel smooth pursuit tasks and quantitative measurement techniques can help unravel the different smooth pursuit components and complex neural systems involved in its control. The maintenance of smooth pursuit is driven by a combination of the prediction of target velocity and visual feedback about performance quality, thus a combination of retinal and extraretinal information that has to be integrated in various networks. Different models of smooth pursuit with specific in- and output parameters have been developed for a better understanding of the underlying neurophysiological mechanisms and to make quantitative predictions that can be tested in experiments. Functional brain imaging and neurophysiological studies have defined motion sensitive visual area V5, frontal (FEF) and supplementary (SEF) eye fields as core cortical smooth pursuit regions. In addition, a dense neural network is involved in the adjustment of an optimal smooth pursuit response by integrating also extraretinal information. These networks facilitate interaction of the smooth pursuit system with multiple other visual and non-visual sensorimotor systems on the cortical and subcortical level. Future studies with fMRI advanced techniques (e.g., event-related fMRI) promise to provide an insight into how smooth pursuit eye movements are linked to specific brain activation. Applying this approach to neurological and also mental illness can reveal distinct disturbances within neural networks being present in these disorders and also the impact of medication on this circuitry.     

Neurophysiology and neuroanatomy of smooth pursuit in humans

Smooth pursuit eye movements enable us to focus our eyes on moving objects by utilizing well-established mechanisms of visual motion processing, sensorimotor transformation and cognition. Novel smooth pursuit tasks and quantitative measurement techniques can help unravel the different smooth pursuit components and complex neural systems involved in its control. The maintenance of smooth pursuit is driven by a combination of the prediction of target velocity and visual feedback about performance quality, thus a combination of retinal and extraretinal information that has to be integrated in various networks. Different models of smooth pursuit with specific in- and output parameters have been developed for a better understanding of the underlying neurophysiological mechanisms and to make quantitative predictions that can be tested in experiments. Functional brain imaging and neurophysiological studies have defined motion sensitive visual area V5, frontal (FEF) and supplementary (SEF) eye fields as core cortical smooth pursuit regions. In addition, a dense neural network is involved in the adjustment of an optimal smooth pursuit response by integrating also extraretinal information. These networks facilitate interaction of the smooth pursuit system with multiple other visual and non-visual sensorimotor systems on the cortical and subcortical level. Future studies with fMRI advanced techniques (e.g., event-related fMRI) promise to provide an insight into how smooth pursuit eye movements are linked to specific brain activation. Applying this approach to neurological and also mental illness can reveal distinct disturbances within neural networks being present in these disorders and also the impact of medication on this circuitry.     

Quantification and analysis of saccadic and smooth pursuit eye movements and fixations to detect oculomotor deficits

Assessment of deficits in oculomotor function may be useful to detect visuomotor impairments due to a closed head injury. Systematic analysis schemes are needed to reliably quantify oculomotor deficits associated with oculomotor impairment via brain trauma. We propose a systematic, automated analysis scheme using various eye-tracking tasks to assess oculomotor function in a cohort of adolescents with acute concussion symptoms and aged-matched healthy controls. From these data we have evidence that these methods reliably detect oculomotor deficits in the concussed group, including reduced spatial accuracy and diminished tracking performance during visually guided prosaccade and self-paced saccade tasks. The accuracy and tracking deficits are consistent with prior studies on oculomotor function, while introducing novel discriminatory measures relative to fixation assessments – methodologically, a less complicated measure of performance – and thus represent a reliable and simple scheme of detection and analysis of oculomotor deficits associated with brain injury.     

Smooth pursuit eye movements are associated with phonological awareness in preschool children

Phonological awareness is strongly related to reading ability, but reports are more conflicting concerning the association of high level oculomotor skills with reading. Here, we show that phonological awareness is specifically associated with the ability to perform smooth pursuit eye movements in preschool children. Two large independent samples of preschool children (n=838 and n=732) aged 5-6.4 years, without history of neurological disorder, were examined by school medical doctors for visual and oculomotor problems. Nineteen percent of the children in the first sample and 14% in the second failed at the clinical evaluation of smooth pursuit eye movements, and 17 and 15%, respectively, presented another visual or oculomotor problem. Ten short cognitive tests were performed by the same children. Visual and oculomotor problems other than a failure on smooth pursuit were not consistently related to the cognitive tasks, with one exception, the visual recognition of letters. Children who failed at smooth pursuit obtained lower scores at a number of cognitive tasks, and especially phonological awareness tasks and copy of visually presented trajectories. Poor working memory and/or failure of anticipation during the tracking of a visual or auditory stimulus related to frontal cortex immaturity may explain these associations in preschool children.     

Alternating Adaptation of Eye and Hand Movements to Opposite Directed Double Steps

Eye and hand movements can adapt to a variety of sensorimotor discordances. Studies on adaptation of movement directions suggest that the oculomotor and the hand motor system access the same adaptive mechanism related to the polarity of a discordance, because concurrent adaptations to opposite directed discordances strongly interfere. The authors scrutinized whether participants adapt their hand and eye movements to opposite directions (clockwise/counterclockwise) when both motor systems are alternatingly exposed to opposite directed double steps, and whether such adaptation is influenced by the allocation of effector to adaptation direction. The results showed that hand and eye movements adapted to opposite directions, but adaptation was biased to the counterclockwise direction. Aftereffects emerged nearly unbiased and independently for both motor systems. The authors conclude that the oculomotor and the hand motor system use independent mechanisms when they adapt to opposite polarities, although they interact during adaptation or concurrent performance.     

The relationship between eye movements and spatial attention

Most previous studies of the attentional consequences of making saccadic eye movements have used peripheral stimuli to elicit eye movements. It is argued that in the light of evidence showing automatic “capture” of attention by peripheral stimuli, these experiments do not distinguish between attentional effects due to peripheral stimuli and those due to eye movements. In the present study, spatial attention was manipulated by varying the probability that peripheral probe stimuli would appear in different positions, while saccades were directed by a central arrow, enabling the effects of attention and eye movements to be separated. The results showed that the time to react to a peripheral stimulus could be shortened both by advance knowledge of its likely position and, separately, by preparing to make a saccade to that position. When the saccade was directed away from the most likely position of the probe, the targets for attention and eye movements were on opposite sides of the display. In this condition, the effects of preparing to make a saccade proved to be stronger than the effects of attentional allocation until well after the saccade had finished, suggesting that making a saccade necessarily involves the allocation of attention to the target position. The effects of probe stimuli on saccade latencies were also examined: probe stimuli that appeared before the saccade shortened saccade latencies if they appeared at the saccade target, and lengthened saccade latencies if they appeared on the opposite side of fixation. These facilitatory and inhibitory effects were shown to occur at different stages of saccade preparation and suggest that attention plays an important role in the generation of voluntary eye movements. The results of this study indicate that while it is possible to make attention movements without making corresponding eye movements, it is not possible to make an eye movement (in the absence of peripheral stimulation) without making a corresponding shift in the focus of attention.     

Kinematic property of target motion conditions gaze behavior and eye-hand synergy during manual tracking

This study investigated how frequency demand and motion feedback influenced composite ocular movements and eye-hand synergy during manual tracking. Fourteen volunteers conducted slow and fast force-tracking in which targets were displayed in either line-mode or wave-mode to guide manual tracking with target movement of direct position or velocity nature. The results showed that eye-hand synergy was a selective response of spatiotemporal coupling conditional on target rate and feedback mode. Slow and line-mode tracking exhibited stronger eye-hand coupling than fast and wave-mode tracking. Both eye movement and manual action led the target signal during fast-tracking, while the latency of ocular navigation during slow-tracking depended on the feedback mode. Slow-tracking resulted in more saccadic responses and larger pursuit gains than fast-tracking. Line-mode tracking led to larger pursuit gains but fewer and shorter gaze fixations than wave-mode tracking. During slow-tracking, incidences of saccade and gaze fixation fluctuated across a target cycle, peaking at velocity maximum and the maximal curvature of target displacement, respectively. For line-mode tracking, the incidence of smooth pursuit was phase-dependent, peaking at velocity maximum as well. Manual behavior of slow or line-mode tracking was better predicted by composite eye movements than that of fast or wave-mode tracking. In conclusion, manual tracking relied on versatile visual strategies to perceive target movements of different kinematic properties, which suggested a flexible coordinative control for the ocular and manual sensorimotor systems.     

Oculomotor inhibition of return in normal and mindless reading

Oculomotor inhibition of return (O-IOR) is an increase in saccade latency prior to an eye movement to a recently fixated location, as compared with other locations. To investigate O-IOR in reading, subjects participated in two conditions while their eye movements were recorded: normal reading and mindless reading with words replaced by geometric shapes. We investigated the manifestation of O-IOR in reading and whether it is related to extracting meaning from the text or is an oculomotor phenomenon. The results indicated that fixation durations prior to a saccade returning to the immediately preceding fixated word were longer than those to other words, consistent with O-IOR. Furthermore, fixation durations were longest prior to a saccade that returned the eyes to the specific character position in the word that had previously been fixated and dropped off as the distance between the previously fixated character and landing position increased. This result is consistent with the hypothesis that O-IOR is relatively precise in its application during reading and drops off as a gradient. Both of these results were found for text reading and for mindless reading, suggesting that they are consequences of oculomotor control, and not of language processing. Finally, although these temporal IOR effects were robust, no spatial consequences of IOR were observed: Previously fixated words and characters were as likely to be refixated as new words and characters.     

Saccadic eye movement programming: sensory and attentional factors

The relationship between attention and eye movements is explored by consideration of the variety of ways attention may affect saccade programming. Four forms of attention are distinguished: one exogenous and three endogenous through either locations or objects or features. Each of these can control or influence the saccadic generation process. Visual onsets generate a rapid transient signal with low resolution that travels from the visual system to the oculomotor system. Generation of an eye movement is associated with an attentional signal, probably also with low resolution, travelling from the oculomotor system to the visual system. A high-resolution attentional signal, which appears to require voluntary effort, can also select saccadic targets.     

A review on eye movement studies in childhood and adolescent psychiatry

The neural substrates of eye movement measures are largely known. Therefore, measurement of eye movements in psychiatric disorders may provide insight into the underlying neuropathology of these disorders. Visually guided saccades, antisaccades, memory guided saccades, and smooth pursuit eye movements will be reviewed in various childhood psychiatric disorders. The four aims of this review are (1) to give a thorough overview of eye movement studies in a wide array of psychiatric disorders occurring during childhood and adolescence (attention-deficit/hyperactivity disorder, oppositional deviant disorder and conduct disorder, autism spectrum disorders, reading disorder, childhood-onset schizophrenia, Tourette’s syndrome, obsessive compulsive disorder, and anxiety and depression), (2) to discuss the specificity and overlap of eye movement findings across disorders and paradigms, (3) to discuss the developmental aspects of eye movement abnormalities in childhood and adolescence psychiatric disorders, and (4) to present suggestions for future research. In order to make this review of interest to a broad audience, attention will be given to the clinical manifestation of the disorders and the theoretical background of the eye movement paradigms.     

A review on eye movement studies in childhood and adolescent psychiatry

The neural substrates of eye movement measures are largely known. Therefore, measurement of eye movements in psychiatric disorders may provide insight into the underlying neuropathology of these disorders. Visually guided saccades, antisaccades, memory guided saccades, and smooth pursuit eye movements will be reviewed in various childhood psychiatric disorders. The four aims of this review are (1) to give a thorough overview of eye movement studies in a wide array of psychiatric disorders occurring during childhood and adolescence (attention-deficit/hyperactivity disorder, oppositional deviant disorder and conduct disorder, autism spectrum disorders, reading disorder, childhood-onset schizophrenia, Tourette’s syndrome, obsessive compulsive disorder, and anxiety and depression), (2) to discuss the specificity and overlap of eye movement findings across disorders and paradigms, (3) to discuss the developmental aspects of eye movement abnormalities in childhood and adolescence psychiatric disorders, and (4) to present suggestions for future research. In order to make this review of interest to a broad audience, attention will be given to the clinical manifestation of the disorders and the theoretical background of the eye movement paradigms.     

Smooth pursuit eye movement and schizotypy in the community

Deficits in smooth pursuit eye movements are well documented in schizophrenia and schizotypic psychopathology. The status of eye tracking dysfunction (ETD) as an endophenotype for schizophrenia liability is relatively robust. However, the relation of ETD to schizophrenia-related deviance in the general population has not been confirmed. This study examined smooth pursuit eye tracking and schizotypal personality features in the general population. Smooth pursuit eye movement and schizotypal features were measured in 300 adult community subjects. The sample included both sexes, subjects with a wide age and educational range, and subjects with no prior history of psychosis. Primary outcome measures were peak gain (eye velocity/target velocity), catch-up saccade rate, and schizotypal feature scores. Total schizotypal features were significantly associated with decreased peak gain and were associated at the trend level with increased catch-up saccade rate. These associations were essentially unchanged after controlling for age, sex, and intellectual level effects. These data confirm a hypothesized association between schizotypal features and poorer eye tracking performance (principally, peak gain) in the general population as well as support the conceptualization of ETD as an endophenotype for schizophrenia liability.     

A revised analysis of the role of efference in motion perception

The analysis of motion perception historically has included efferent as well as afferent mechanisms to account for the perception of motion during eye movement. The application of efferent mechanisms to motion perception has been limited, however, by several illusions which are apparently inconsistent with the notion that oculomotor mechanisms contribute to motion perception. An alternative account is presented of the manner in which efference may contribute to the perception of motion. It is proposed that distinct smooth eye-movement systems contribute differentially to object motion perception. Specifically, activity in the smooth pursuit system gives rise to the perception of object motion, whereas activity in the smooth component of reflexive eye movements does not. Tracking of a moving object results in object motion perception as a result of efference in the pursuit system. However, the pursuit system may be activated to oppose the smooth component of reflexive eye movements in order to preserve fixation on a stationary object. In such cases neither the fixated object nor the eye is moving but illusory movement results from the efference in the pursuit system. A number of illusory movement phenomena are interpreted in terms of this model.     

How memory mechanisms are a key component in the guidance of our eye movements: Evidence from the global effect

Investigating eye movements has been a promising approach to uncover the role of visual working memory in early attentional processes. Prior research has already demonstrated that eye movements in search tasks are more easily drawn toward stimuli that show similarities to working memory content, as compared with neutral stimuli. Previous saccade tasks, however, have always required a selection process, thereby automatically recruiting working memory. The present study was an attempt to confirm the role of working memory in oculomotor selection in an unbiased saccade task that rendered memory mechanisms irrelevant. Participants executed a saccade in a display with two elements, without any instruction to aim for one particular element. The results show that when two objects appear simultaneously, a working memory match attracts the first saccade more profoundly than do mismatch objects, an effect that was present throughout the saccade latency distribution. These findings demonstrate that memory plays a fundamental biasing role in the earliest competitive processes in the selection of visual objects, even when working memory is not recruited during selection.     

阅读水平调节儿童阅读眼动注视模式的发展:基于9～11岁儿童的证据

按照3~5年级小学生的语文阅读水平,在各年级中分别选取年龄相同的高、中、低三组儿童作为被试,要求他们阅读适合本年级阅读水平的5篇短文,探讨同一年龄段内读者阅读水平的高低对阅读眼动注视模式的影响是否存在发展上的差异。通过记录其眼动轨迹,结果发现:9岁儿童的阅读眼动注视模式受读者本身阅读水平的影响最大,10岁次之,到11岁,随着儿童基本眼动行为的成熟,这种影响随之消失。表明读者阅读眼动注视模式的发展动力来源于语言操作技能和眼球运动协调性提高的交互作用。     

Updating the premotor theory: The allocation of attention is not always accompanied by saccade preparation

There is an ongoing controversy regarding the relationship between covert attention and saccadic eye movements. While there is quite some evidence that the preparation of a saccade is obligatory preceded by a shift of covert attention, the reverse is not clear: Is allocation of attention always accompanied by saccade preparation? Recently, a shifting and maintenance account was proposed suggesting that shifting and maintenance components of covert attention differ in their relation to the oculomotor system. Specifically, it was argued that a shift of covert attention is always accompanied by activation of the oculomotor program, while maintaining covert attention at a location can be accompanied either by activation or suppression of oculomotor program, depending on the probability of executing an eye movement to the attended location. In the present study we tested whether there is such an obligatory coupling between shifting of attention and saccade preparation and how quickly saccade preparation gets suppressed. The results showed that attention shifting was always accompanied by saccade preparation whenever covert attention had to be shifted during visual search, as well as in response to exogenous or endogenous cues. However, for the endogenous cues the saccade program to the attended location was suppressed very soon after the attention shift was completed. The current findings support the shifting and maintenance account and indicate that the premotor theory needs to be updated to include a shifting and maintenance component for the cases in which covert shifts of attention are made without the intention to execute a saccade. (PsycINFO Database Record (c) 2012 APA, all rights reserved).     

Scrutinization, Spatial Attention, and the Spatial Programming of Saccadic Eye Movements

Results are presented from an experiment in which subjects' eye movements were recorded while they carried out two visual tasks with similar material. One task was chosen to require close visual scrutiny; the second was less visually demanding. The oculomotor behaviour in the two tasks differed in three ways. (1) When scrutinizing, there was a reduction in the area of visual space over which stimulation influences saccadic eye movements. (2) When moving their eyes to targets requiring scrutiny, subjects were more likely to make a corrective saccade. (3) The duration of fixations on targets requiring scrutiny was increased. The results are discussed in relation to current theories of visual attention and the control of saccadic eye movements.     

Oculomotor atypicalities in Developmental Coordination Disorder

Children with Developmental Coordination Disorder (DCD) fail to acquire adequate motor skill, yet surprisingly little is known about the oculomotor system in DCD. Successful completion of motor tasks is supported by accurate visual feedback. The purpose of this study was to determine whether any oculomotor differences can distinguish between children with and without a motor impairment. Using eye tracking technology, visual fixation, smooth pursuit, and pro‐ and anti‐saccade performance were assessed in 77 children that formed three groups: children with DCD (aged 7–10), chronologically age (CA) matched peers, and a motor‐match (MM) group (aged 4–7). Pursuit gain and response preparation in the pro‐ and anti‐saccade tasks were comparable across groups. Compared to age controls, children with DCD had deficits in maintaining engagement in the fixation and pursuit tasks, and made more anti‐saccade errors. The two typically developing groups performed similarly, except on the fast speed smooth pursuit and antisaccade tasks, where the CA group outperformed the younger MM group. The findings suggest that children with DCD have problems with saccadic inhibition and maintaining attention on a visual target. Developmental patterns were evident in the typically developing groups, suggesting that the pursuit system and cognitive control develop with age. This study adds to the literature by being the first to systematically identify specific oculomotor differences between children with and without a motor impairment. Further examination of oculomotor control may help to identify underlying processes contributing to DCD. A video abstract of this article can be viewed at: https://youtu.be/NinXa2KlB4M . [Correction added on 27 January 2017, after first online publication: The video abstract link was added.]