History and Future Directions of Vision Testing in Head Trauma

State-of-the-Art Review Section Editors: Fiona Costello, MD, FRCP(C) Sashank Prasad, MD History and Future Directions of Vision Testing in Head Trauma Omar Akhand, BS, John-Ross Rizzo, MD, MSCI, Janet C. Rucker, MD, Lisena Hasanaj, MPA, Steven L. Galetta, MD, Laura J. Balcer, MD, MSCE Background: Concussion leads to neurophysiologic changes that may result in visual symptoms and changes in ocular motor function. Vision-based testing is used increasingly to improve detection and assess head injury. This review will focus on the historical aspects and emerging data for vision tests, emphasizing rapid automatized naming (RAN) tasks and objective recording techniques, including video-oculography (VOG), as applied to the evaluation of mild traumatic brain injury. Methods: Searches on PubMed were performed using combinations of the following key words: "concussion," "mild traumatic brain injury," "rapid automatized naming," "King-Devick," "mobile universal lexicon evaluation system," "video-oculography," and "eye-tracking." Additional information was referenced from web sites of vendors of commercial eye-tracking systems and services. Results: Tests of rapid number, picture, or symbol naming, termed RAN tasks, have been used in neuropsychological studies since the early 20th century. The visual system contains widely distributed networks that are readily assessed by a variety of functionally distinct RAN tasks. The King-Devick test, a rapid number naming assessment, and several picture-naming tests, such as the Mobile Universal Lexicon Evaluation System (MULES) and the modified Snodgrass and Vanderwart image set, show capacity to identify athletes with concussion. VOG has gained widespread use in eye- and gaze-tracking studies of head trauma from which objective data have shown increased saccadic latencies, saccadic dysmetria, errors in predictive target tracking, and changes in vergence in concussed subjects. Performance impairments on RAN tasks and on tasks recorded with VOG are likely related to ocular motor dysfunction and to changes in cognition, specifically to attention, memory, and executive functioning. As research studies on ocular motor function after concussion have expanded, so Departments of Neurology (OA, JRR, LH, SLG, LJB), Population Health (LJB), Ophthalmology (SLG, LJB), and Physical Medicine and Rehabilitation (JRR), New York University School of Medicine, New York, New York. L. J. Balcer has received investigator-initiated research grant funding from Biogen. The remaining authors report no conflicts of interest. Address correspondence to Laura J. Balcer, MD, MSCE, Department of Neurology, New York University School of Medicine, 240 East 38th Street, 20th Floor, New York, NY 10016; E-mail: laura.balcer@ nyumc.org 68 too have commercialized eye-tracking systems and assessments. However, these commercial services are still investigational and all vision-based markers of concussion require further validation. Conclusions: RAN tasks and VOG assessments provide objective measures of ocular motor function. Changes in ocular motor performance after concussion reflect generalized neurophysiologic changes affecting a variety of cognitive processes. Although these tests are increasingly used in head injury assessments, further study is needed to validate them as adjunctive diagnostic aids and assessments of recovery. Journal of Neuro-Ophthalmology 2019;39:68-81 doi: 10.1097/WNO.0000000000000726 © 2018 by North American Neuro-Ophthalmology Society C oncussion is a form of mild traumatic brain injury (mTBI) incurred through direct or transmitted impulses to the head, resulting in functional brain injury (1). Sports-related concussion (SRC) represents a significant component of TBI, with an estimate by the Centers for Disease Control of 1.6-3.8 million annual cases occurring in the United States (2). This figure was extrapolated from emergency department data and includes cases for which no medical care was sought. Despite being categorized as "mild" TBI, SRCs are not benign and may result in second-impact syndrome or long-term symptoms. Furthermore, repetitive head impacts are now being investigated as a potential cause of chronic traumatic encephalopathy (3- 7). Symptom underreporting adds diagnostic complexity, as athletes surreptitiously attempt to regain clearance and return to play (RTP) (8). These factors have established a need for objective measures that are readily performed on the sidelines; such assessments would add objective data to RTP decisions and may prevent devastating complications of repeated head injury. Vision-based assessments have emerged as promising adjuncts in the evaluation of TBI. Most sports organizations have not yet incorporated objective visual tests into their Akhand et al: J Neuro-Ophthalmol 2019; 39: 68-81 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review injury protocols likely due to obstacles including need for further validation, demonstration of reproducibility, and the costs of addition equipment and training. Yet, reports have shown that combining such assessments with commonly used sideline tools such as the SCAT 5 and ImPACT improves detection of concussion among athletes (9-12). Because approximately 50% of brain circuitry is involved in visual information gathering and processing (9,10), objective measurements of visual performance are likely to detect brain dysfunction. Clinical testing of the efferent visual system in patients with TBI has been performed mainly by "rapid automatized naming" (RAN) tasks that consist of timed and scored letter, number, color, or picture/ object identification (13-17). Video-oculographic (VOG) recordings of eye movements have revealed quantitative changes in ocular motor performance in concussed subjects (18-26). RAN tasks and VOG-based paradigms have integrated aspects of cognition and executive function such as object/semantic categorization, language, task switching, attention/concentration, and memory (11,27). The focus of this review is to examine the historical perspectives and emerging data for RAN tasks and VOG-integrated visual assessments in concussion. RAPID AUTOMATIZED NAMING TASKS Historical Background In RAN tasks, subjects are asked to read letters, digits, objects, or other visual stimuli such as colors or geometric shapes as quickly as possible. These tasks were initially implemented in reading behavior and child development studies. Over 80 years ago, Card and Wells (13) studied the use of RAN in healthy children. Their tests of timed number, letter, object, and color naming integrated verbal and visual skills and demonstrated correlations to reading ability (Fig. 1). This foundational work not only provided normative data for several RAN tasks but also began to uncover functional distinctions in color, word, and object perception. Subsequently, Gilbert (15) devised a rapid number naming test that included the staggering of numbers to assess reading speeds in various cohorts of school-aged children (Fig. 1). In this VOG investigation, Gilbert was able to correlate high reading scores with low rates of brief fixations and backward saccades. Perhaps, the first example of RAN tasks applied to the evaluation of concussed patients is found in a 1944 study by Ruesch (16) of neurological recovery from head trauma. Among the wide variety of established psychometric tests and novel tasks he used, naming of colors, reading, and fatigue scores emerged as measures that showed the most improvement in the greatest number of patients recovering from TBI. He also identified mental processing speed, visual perception, and concentration as key testable traits that demonstrated marked changes in performance. These Akhand et al: J Neuro-Ophthalmol 2019; 39: 68-81 tests were then incorporated into the Mental Examiners Handbook, a publication that survived many editions to the year 1969 (17). The Pierce test was created in 1972 and comprised 4 different cards that subjects would read by rapidly shifting their eyes between 2 columns of numbers (28). It would lead to creation of the King-Devick (KD) test, a rapid number naming test initially developed in 1976 to test reading and later applied to the assessment of concussion. Since then, RAN tasks have expanded to include object-naming tasks such as the modified Snodgrass and Vanderwart's (S&V) image set (29) and the Mobile Universal Lexicon Evaluation System (MULES) (Fig. 1) (30,31). Number-Based Rapid Automatized Naming Tasks and the King-Devick Test The most widely adopted RAN task in concussion testing has been the KD test. Before the KD test was the Pierce saccade test, which consisted of 4 cards, each with 2 aligned columns of numbers forming 15 horizontal pairs (28) (Fig. 1). Subjects make saccades to look back and forth between the left- and right-hand digits spaced far apart on the cards. Participants performing the KD test are asked to read each of 3 cards as quickly as possible. The times to read the 3 cards are summed into a total score and the number of errors made is recorded. Two baseline trials are administered and the better of the 2 is used as reference for postinjury performance. An increase in the time needed to read all 3 cards after injury is consistent with concussion. Reports of test reliability have varied across studies seeking to validate the KD test. Lieberman and colleagues obtained normative data for the KD in 1983. They administered the test to a group of children of ages 6 to 14 years but did not address test-retest variability (32). The first report of test reliability came from Oride et al (33) who performed a comparison of the Pierce and KD tests and showed both to have poor reliability because of the significant improvement observed with repeat testing. Further evaluation of the KD's reliability was published recently by Oberlander et al (34), who administered the KD to a group of 68 healthy adolescents. Contrary to previous data, they found an acceptable measure of reliability with an intraclass correlation coefficient (ICC) of 0.81. Yet, in agreement with previous findings, significant learning effects were appreciated; this was true even after a third trial administered 45 days after the first. Given these large learning effects, it has become standard to administer multiple trials at baseline. The Oberlander study suggests that administering the KD twice at baseline may not fully account for learning effects. This concern has been further supported by a recent study of 10 concussed NCAA athletes who failed to show any significant changes acutely (24-48 hours after injury) or at the time of RTP, despite adopting standard KD testing procedures (35). In fact, 6 subjects showed improvement acutely and 7 showed improvement at the time of RTP. 69 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review FIG. 1. Rapid automatized naming (RAN) tasks. (A) Color Naming and Gilbert's Test; (B) Pierce Saccade Test and Modified Snodgrass Test; (C) Mobile Universal Lexicon Evaluation System (MULES). KD, King-Devick. 70 Akhand et al: J Neuro-Ophthalmol 2019; 39: 68-81 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review Clearly, learning effects influenced the study's results. Another study administered 3 trials of the KD to 60 healthy participants, rather than the standard 2 trials at baseline (36). The authors showed that the addition of a third trial at baseline maintained significant decreases in times (improved performance) across all trials. Eliminating the first trial improved the intraclass correlation from 0.95 to 0.97. Furthermore, age and sex were found to be significant factors of baseline performance. Although test-retest reliability may still require further investigation, it is well established that learning effects must be taken into account to ensure that data are interpretable. However, the exact methodologies for doing so may need further development. The strongest supporting evidence validating the KD test came from Galetta et al (37), beginning in 2011, when the group analyzed data from a cohort of 39 mixed martial arts fighters and boxers. Scores worsened by a median of 11 seconds in fighters with head trauma, with especially poor times measured in fighters who lost consciousness. Postinjury increases from baseline of 5 seconds on average were seen among those with head trauma. The cohort demonstrated high test-retest reliability, with an intraclass correlation of 0.97. Galetta et al (38) further investigated the use of the KD in a larger, follow-up cohort of 219 collegiate and youth athletes, among whom 10 sustained concussions. The concussed group demonstrated an average worsening from baseline scores by 5.9 seconds. In 2015, a third cohort of 332 collegiate and youth athletes including 12 subjects who incurred concussions was investigated (39). These 12 athletes likewise demonstrated an average increase in score of 5.2 seconds from baseline. This report included data that compared KD scores with those of the Standardized Assessment of Concussion (SAC) and timed tandem gait. The KD had the greatest capacity to distinguish concussed and control groups, accounting for age. Combined KD and tandem gait scores demonstrated an area under the receiver operating characteristic (ROC) curve of 0.98, compared with an area of 0.92 under the KD-only ROC curve. A recent study of ocular motor testing adopted a threshold of 5.2 seconds for identifying concussion; this had been the mean increase in scores from baseline. Eight of 13 concussed athletes had postinjury KD times that exceeded this limit (40). By contrast, most previous studies had designated any worsening of KD time score to be indicative of concussion. In 2016, a meta-analysis of 15 KD-based studies for a pooled total of 112 concussed athletes was completed. The report showed the KD to have 86% sensitivity and a 90% specificity for detecting concussion (41). Among 1,419 athletes, the estimate of the preseason KD baseline was 43.8 seconds (95% CI: 40.2-47.5); the I2 value was 0.0% (P = 0.85), indicating very little heterogeneity between the 15 studies for which primary data were obtained. Among 112 athletes with concussion, weighted estimates for postinjury changes in KD from preseason or prematch baseline showed a worsening (increased time) of Akhand et al: J Neuro-Ophthalmol 2019; 39: 68-81 4.8 seconds (95% CI: 3.7-5.8). The I2 value for this analysis was also 0.0% (P = 0.58), again indicating very little heterogeneity and good consistency between studies. Nonconcussed control athletes demonstrated an average improvement of 1.9 seconds (95% CI: 23.6 to 20.02; I2 0.0%, P = 0.99). In summary, the KD test is a rapid number naming test that is easily performed on the sidelines to detect concussion. It tests ocular motor function and cognitive features such as attention and speech. As for any performance-based measure, it is important to account for learning effects by conducting at least 2 trials at baseline. Pooled data from multiple studies suggest good sensitivity and specificity based on any increase from preseason baseline at the time of concussion. Object-Based Rapid Automatized Naming Tasks and the Mobile Universal Lexicon Evaluation System Various types of RAN tests used throughout the 20th century have demonstrated functional differences and assess a wide network of neural systems (13,14,16,42-45). One well-established image data set often used in behavioral experiments is the S&V image bank. This consists of 260 line drawings of objects with documented norms for name agreement, image agreement, naming latency, familiarity, and complexity ratings (46). Many investigators researching various domains of cognition and vision have adopted images from this set. Rossion and Pourtois (28) modified this image set in their research on object recognition by creating colored and realistic versions of the original S&V line drawings. Their work showed that the updated versions of the S&V line drawings, containing color and surface texture information, were more easily recognizable than the original line drawings. They inferred that edge information is integrated with color and surface information during object perception. The modified S&V image set was used in a recent study of object-based RAN testing in 58 participants of ages 10-22 years, 32 of whom suffered a concussion in the previous month (47). As the authors had predicted, concussed subjects performed more slowly on the objectnaming tasks compared with age-matched controls. This difference in performance was apparent only in subjects within 2 weeks of injury. Subjects evaluated 3 weeks after injury were indistinguishable from controls. Error rates, on the other hand, did not differ between groups. Recovery trajectories based on task performance suggest a 10-20day course. The MULES was developed to test other visual domains including object recognition and naming, color detection, and categorization. The MULES is composed of 54 original color photographs of various fruits, common items, and animals. Its usage of color photographs in context was informed by the studies examining the role of color, surface, and contextual information in the perception of objects. In the long tradition of object-based RAN tasks, the MULES 71 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review test incorporates eye movements, semantic identification, phonology, and articulation (42-45,48). The first study, published in 2017, describes baseline characteristics of the MULES test in a cohort of 20 adult volunteers (30). Subjects demonstrated characteristic learning effects between trials. A subsequent study in a much larger cohort of 501 adult office staff as well as collegiate and youth athletes sought to characterize a reformatted version of the MULES test, which had been scaled down to a double-sided laminated paper for sideline use (29). The new version, which was equivalent to the previous format in terms of baseline mean scores and learning effects, showed strong age dependence among younger participants, possibly reflective of developmental trajectory. Athletes who completed both versions of the MULES demonstrated high intertest agreement with an ICC of 0.90. The second MULES study also provided preliminary evidence for worsening of time scores postinjury compared with a preseason baseline among 6 athletes with concussion (average of 4-second worsening, P = 0.003, the Wilcoxon signed-rank test). Future investigations and postinjury analysis are required to validate the MULES as a sideline and clinical test for concussion. Functional Differences Between Rapid Automatized Naming Tasks There is accumulating evidence that not all RAN tasks are equivalent. Functional distinctions between these tasks are supported by behavioral data from psychological studies and by case reports of patients in which word, face, and object recognition have been dissociated (49-51). The seminal work by Card and Wells (13) on RAN task performance in children revealed that word reading and color naming were similarly impaired in the "reading-problem children." Interestingly, these same children performed better on object naming compared with their peers in the same grade level without reading difficulties. Clinical data have spurred debate over whether object recognition is a diffusely distributed process involving perceptual integration of object features or a global "gestalt" mechanism. These differing views of perception have consequential implications regarding localization of object, color, and symbol processing. For example, many investigators have argued that the combination of alexia and prosopagnosia inextricably leads to object agnosia (52), although this has been challenged (49,50). Interestingly, in patients with clinical syndromes of alexia without agraphia, which are usually due to left-sided posterior cerebral artery infarcts of the calcarine cortex and splenium of the corpus callosum, reading and color naming are impaired while recognition and naming of objects and numbers are spared (14). This syndrome recapitulates the RAN task performance of children with alexia as described by Card and Wells and emphasizes the differences in functional connectivity between regions involved in word, color, number, and object naming. 72 Evidence differentiating various RAN tasks has also been provided by functional imaging studies demonstrating that the neural networks recruited by these tests depend on the type of RAN task. In an fMRI study of 15 university students comparing digit and letter-based RAN tasks against object-based RAN tasks, significant overlap and key differences were found in neural activation patterns (53). Alphanumeric RAN tasks preferentially activated the cuneus, precuneus, nucleus accumbens, thalamus, left angular gyrus, supplementary motor association cortex, and bilateral superior temporal gyrus; all these regions are involved in reading (54). Object-based RAN tasks preferentially activated the bilateral fusiform gyri, which are involved in form recognition, especially for faces (53,55). Overall, activation patterns of alphanumeric RAN tasks closely resembled that of reading and were associated with reading performance metrics. VIDEO-OCULOGRAPHY Historical Background The earliest recordings of eye movements date to the late 19th century (56-58). However, research in this area rapidly expanded after the studies of Dodge and Cline (59). Although scleral search coils have been the gold-standard means of eye-tracking, electro-oculography and dualPurkinje trackers also have been used. However, infrared video-based recordings using corneal reflections and pupiltracking have gained widespread use in concussion research, as such methods are less invasive, have shorter set-up times, and demonstrate comparable spatial and temporal resolution (60-63). VOG was first applied to the study of TBI in the 1990s, mostly in cases of severe injuries resulting in coma (26,64). The VOG methods and assessments described in the following sections are all under investigation and have not been FDA approved for the diagnosis of concussion or TBI. Although such techniques would complement historical and clinical findings with objective data, their use on the sidelines or at the bedside will require standardized methodology, improved portability, and trained personnel capable of interpreting the results. Ocular Motor Findings in Video-Oculography Studies of Concussion: Saccades Many eye movement studies use well-established reflexive and voluntary, saccade-based tasks (18-24) (Table 1). In simplified terms, visually guided saccades to suddenly appearing targets are reflexively generated by the parietal eye fields, whereas voluntary saccades are primarily generated by the frontal eye fields (65). Higher cortical control of saccades may be tested by memory-guided saccades and antisaccades. The former requires subjects to look to the remembered location of a previously flashed peripheral stimulus. The latter requires subjects to inhibit a visually driven impulse and look instead at the estimated mirror Akhand et al: J Neuro-Ophthalmol 2019; 39: 68-81 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review TABLE 1. Common paradigms of video-oculography experiments Eye Movement Type Saccades VOG Task Visually driven saccades Visually cued saccades Gap saccades Memory-guided saccades Antisaccades Smooth pursuit Unidirectional sinusoidal oscillator or circular predictive tracking Vergence Disparity vergence Fixation disparity Task Description Cognitive Functions Tested Anatomical Pathway/ Localization Sudden removal of fixation Not applicable; Reflexively generated by target and appearance of reflexive. parietal eye fields peripheral saccadic (10,27,65) target. Intentionally generated by Subject fixates on a central Attention and working memory frontal eye fields. Signals target, and then, a cue are then sent either indicates the possible directly to gaze centers location of an upcoming for horizontal or vertical target. Then, a saccadic gaze, the PPRF and riMLF, target appears, which respectively, or signals may be congruent or are relayed to gaze incongruent to the cue. centers through superior colliculus (10,27,65) Modulation of visual cortical Subject fixates on 1 target, Attentional modulation of areas, particularly V4, by which then extinguishes, saccades the frontal eye fields may and the subject orients to enhance stimulus signals a peripheral target after (90) a variable period. Not well understood. Working and Subject focuses on Possible role for visuospatial a central target while dorsolateral prefrontal memory a peripheral target is cortex, superior temporal flashed. After variable gyrus, and/or inferior delay, the subject is frontal gyrus (91) asked to fixate by memory on where the peripheral target was located. Subject is asked to look Executive function Additionally requires away from the presented dorsolateral prefrontal saccadic target, onto the cortex (66) corresponding mirror location. Subject tracks an object on Attention, working Descending pathways from memory, and a known trajectory, i.e., temporo-parieto-occipital anticipation a circle. Target may be junction and frontal eye transiently extinguished, fields connect in the pons which is termed "target and innervate the blanking" cerebellum, which in turn, sends signals to abducens nuclei (27,65) Not well understood. Requires use of haploscope Not applicable Possible role of to present convergent or mesencephalic reticular divergent step stimuli. formation or nucleus Each eye is presented to reticularis tegmenti stimuli disparately. pontis (92) Not applicable Not well understood. Disparity between gaze Possible role of positions or vergence mesencephalic reticular angles of each eye during formation or nucleus stimulus presentation reticularis tegmenti pontis (92) PPRF, paramedian pontine reticular formation; riMLF, rostral interstitial nucleus of the medial longitudinal fasciculus; VOG, video-oculography. Akhand et al: J Neuro-Ophthalmol 2019; 39: 68-81 73 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review locations of peripherally flashed stimuli. Inhibition of visually driven saccadic impulses during the antisaccade task requires the dorsolateral prefrontal cortex (66). Volitional saccades may also be tested through a self-paced saccade paradigm, in which the subject is instructed to make saccades as quickly as possible between 2 constant targets. One of the earliest VOG studies in TBI was conducted in 1997 by Williams et al (26) who recorded a cohort of 16 patients, aged 18-45 years, recovering from severe TBI. These patients had been injured less than 1 year prior and were compared with age-matched controls (26). Patients demonstrated more square wave oscillations during fixation, longer saccadic latencies, more hypometria during visually guided saccades, fewer saccades on self-paced saccade testing, and higher errors on both memory-guided and antisaccade testing. Abnormalities of saccades have also been reported in mild TBI, such as in the series of experiments performed by Heitger et al (19,20,22,25,67). Generally, patients with mild TBI tend to have greater impairments on higher cortical saccade tasks such as memory-guided saccades and antisaccades, as opposed to reflexive visually guided saccade tasks; these impairments manifest as increased saccadic latencies and higher error rates. Heitger et al (22) also showed these findings to be true in symptomatic patients with prolonged symptoms of concussion. Saccades have also been examined in subjects performing the KD test under VOG recording (25,69). Although KD test times tend to worsen after concussion, the exact mechanisms of these performance decrements had not been elucidated until VOG methods allowed for closer analysis. Rizzo and colleagues (68) recorded eye movements of 12 healthy subjects undergoing a digitized KD test using infrared-based VOG. In their first methodological report, they segregated task-related saccades that are in line with KD reading direction from all other saccades. Then, they subdivided task-related saccades into horizontal saccades (purely horizontal eye movements of at least 2°) and oblique saccades (eye movements with simultaneous horizontal components of at least 10° and downward components of at least 0.5°), which are made when moving to the next row of numbers. This study established normative measures of saccadic peak velocity, amplitude and duration, intersaccade intervals, and distributions for horizontal, oblique, and retrograde saccades. Recorded saccades demonstrated normal relationships between saccade amplitude and peak saccade velocity and between saccade amplitude and saccade duration (i.e., normal main sequence relationships) that were consistent with previously reported normative data. Rizzo et al (25) later applied this analysis to a cohort of chronically concussed subjects, who showed prolonged "inter-saccadic intervals" (ISI; the summed period of fixation and saccadic latency), less accurate saccadic endpoints, higher number of saccades (especially saccades 74 ,8°), and more non-task-related saccades. Furthermore, ISI times and number of saccades made were correlated with overall KD test times. Interestingly, saccadic kinematics and main sequences were indistinguishable from those of controls (i.e., saccades were not slow in concussion), suggesting that physiological changes of concussion spare the brainstem centers controlling saccadic velocity. Marked prolongations in ISI may occur due to prolongation of saccade initiation (i.e., prolonged saccadic latencies) or due to delays in cognition or attention. How these processes are differentially affected in concussion is not yet understood. Smooth Pursuit Much like the tasks assessing volitional saccades, targettracking tasks also involves higher cognitive functions including attention, anticipation, and working memory (69) (Table 1). Pursuit eye movements are governed by a widely distributed neural network involving cortical, brainstem, and cerebellar pathways (70). These eye movements may also demonstrate changes in concussed patients. Traditionally, smooth pursuit eye movements were analyzed in horizontal and vertical planes. Umeda and Sakata (71) developed a task of predictive target tracking that consisted of a target moving in a circular trajectory for simultaneous assessment of the horizontal and vertical components of smooth pursuit tracking (71). Their protocol overcame earlier recording artifacts induced by eyelid movements and would serve as the basis for later VOG studies assessing smooth pursuit eye movements in concussion. Suh and colleagues (72,73) applied Umeda's paradigm to compare smooth pursuit eye movements in patients with mild TBI to those of control subjects. Subjects with mTBI demonstrated impaired target prediction as seen by increased phase lag when tracking the target moving along a circular trajectory. The mTBI group also showed increased positional error, increased intraindividual positional variability, and greater numbers of corrective saccades. These findings are more pronounced when momentarily extinguishing the stimulus, also referred to as "target blanking." Maruta and colleagues (74) sought to correlate positional error in the same predictive tracking task with fractional anisotropy (FA) measured on diffusion tensor imaging. They found that position error in tracking corresponded to abnormal mean FA values in the white matter tracts often involved in mTBI, including the right anterior corona radiata, left superior cerebellar peduncle, and the genu of the corpus callosum. Currently, commercialized portable eye-tracking devices and software (see next section) use the circular predictive tracking paradigm in their assessment of concussion. However, many of these devices still lack FDA clearance and are under investigation. Akhand et al: J Neuro-Ophthalmol 2019; 39: 68-81 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review Vergence and Fixation Disparity Vergence dysfunction is common in patients with mild TBI (Table 1). Studies of ocular motor and visual symptoms in veterans with TBI estimate prevalence of convergence insufficiency (CI) from 47% to 64% (75-78). However, VOG assessments of vergence in concussion are few. Vergence describes disconjugate eye movements typically in the horizontal plane with convergence involving the simultaneous adduction of each eye to fixate on near targets and divergence involving the relative abduction of both eyes for fixation on far targets. A traditional clinical measure of convergence is the near-point-of-convergence (NPC) (27). Normal values of NPC range from 5 to 10 cm, with longer distances suggesting CI. Because typical eye movement recording conditions involve subjects observing stimuli presented twodimensionally at fixed distances on digital screens, assessing fixation at varied depths is difficult without additional equipment. An ideal set-up for convergence assessment requires haploscopes, devices with mirrors arranged to reflect projected stimuli disparately to each eye, to stimulate disparity vergence. This apparatus allows investigators to present step vergence stimuli while maintaining constant focal length, thereby maintaining constant accommodative demand. The application of this design to the study of concussion comes from a pilot study that used objective VOG measures to assess the effect of office-based vision therapy (OBVT) on 5 subjects with concussion-related CI (79). Using VOG recordings, subjects were presented with 4° step convergence and divergence stimuli at both near and far ranges, before and after OBVT. Their far- and nearconvergence responses demonstrated improvements in peak velocities and accuracy with OBVT. Divergence also improved in peak velocity and accuracy for far movements and improved in peak velocity only for near movements. Although averaged convergence and divergence main sequences were impaired initially in these subjects, their averaged saccade main sequences were not affected. This study was the first to use objective markers of disparity vergence to monitor treatment effects of vision therapy and paves the way for other VOG-based objective markers to be used as endpoints in trials. Other investigators have developed methods for assessing fixation disparity between the gaze positions or between the calculated vergence angles of both eyes (8082). One study compared vergence eye movements between groups of participants with structural brain injury, concussion, and non-head-injured and healthy controls (83). Disconjugacy was measured by tracking eye position, rather than through calculations involving gaze position or vergence angles. Subjects viewed a box containing a running video clip moving along the edges of the monitor. "CT negative and CT positive" head-injured patients demonstrated significantly increased total horiAkhand et al: J Neuro-Ophthalmol 2019; 39: 68-81 zontal disconjugacy compared with controls. Horizontal disconjugacy was correlated with symptom severity and cognitive assessment scores on the SAC. Of note, Maruta challenged the methodology of this study in a recently published statement (83). VOG studies of vergence in concussion are still lacking likely due to technical challenges as well as disagreement on testing methodology. Vestibular Function and Nystagmus Nystagmus and vestibular dysfunction may result from mild TBI, although less commonly than saccadic dysfunction or convergence and accommodation insufficiency (84,85). Objective measures of nystagmus in patients with TBI are obtained using electronystagmography and video-nystagmoscopy, usually with goggles or headmounted systems built with infrared VOG (86-88). These mobile systems allow clinicians to compare nystagmus in each eye across different positions; a critical feature in the evaluation of vestibular function. Central causes of nystagmus may be due to cerebellar dysfunction resulting in direction-changing jerk nystagmus whose fast phase may occur in any direction and can be enhanced with fixation (89). Peripheral nystagmus may be due to labyrinthine or vestibulocochlear nerve dysfunction, which produces unidirectional, horizontal, or horizontal-torsional nystagmus that is suppressed by fixation. Frenzel goggles, which impede fixation with high-powered lenses, are useful in determining the influence of fixation on nystagmus. Commercialized Video-Oculography Devices and Assessments Eye-tracking systems vary in their ability to track binocularly, in their portability and restraints on head motion, optimal camera-eye distances, and in temporal and spatial resolution of tracking data. Several eye-tracking systems also integrate multimodal sensors such as for speech identification, facial recognition, or head tracking. Generally, eyetracking systems fall into 3 categories: desktop-mounted, head-mounted, and integrated virtual reality (VR) headsets (Table 2). Scientific studies of ocular motility have often turned to table- or remote-mounted recording devices, as these configurations provide the highest spatial and temporal resolution of pupil and gaze positions. In such arrangements, subjects are seated at a desk and stabilized with a headrest, while performing a task that is run on a fixed digital display in front of them. Head-mounted devices provide the ability to map gaze position onto scene features through the use of separate cameras for the eyes and environment. The allowance for full head movement, scene viewing, and testing at remote locations are ideal for studies of visual attention and for recording real-world tasks. These portable systems have spatial and temporal resolutions lower than those of desktop configurations and are often wired to a laptop or a storage device worn by the subject. Integrated VR headsets deliver controlled visual stimuli while 75 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. TABLE 2. Eye-tracking hardware and specifications State-of-the-Art Review 76 Akhand et al: J Neuro-Ophthalmol 2019; 39: 68-81 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. TABLE 2. Continued State-of-the-Art Review Akhand et al: J Neuro-Ophthalmol 2019; 39: 68-81 77 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. 78 VR, virtual reality. Desktop/remote mounted. Head mounted for scene viewing. Head-mounted VR device with integrated eye tracking. TABLE 2. Continued State-of-the-Art Review Akhand et al: J Neuro-Ophthalmol 2019; 39: 68-81 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review recording eye movements with integrated cameras. Although these devices are the most portable and require the least time and expertise to set-up, they also provide the lowest spatial and temporal resolution of data. Several companies have begun to offer VOG assessments of ocular motility to the public and to clinicians. The EyeSync assessment offered by SyncThink uses an integrated Gear VR headset that presents subjects with the predictive circular eye-tracking task developed by Maruta et al. It is marketed as "FDA approved to record and analyze eye-tracking impairment" and adopted by Stanford University's athletics department. However, its use in concussion assessment is still under investigation and has not been FDA approved for concussion diagnosis or assessment. Another company, RightEye, offers an ocular motor assessment called EyeQ, which is a portable, monitor-based test integrated with VOG. Subjects are presented with a series of tasks assessing circular, horizontal, and vertical smooth pursuit, volitional saccades, choice reaction times, and fixation stability. RightEye markets this service as useful to athletes who want to improve their performance, parents who want to ensure their children develop normally, and to clinicians in the identification of various pathologies including concussion, autism, stroke, Parkinson disease, and binocular vision issue leading to reading impairments in children. The company does state that the EyeQ is an investigational assessment and has not received FDA clearance. CONCLUSIONS Researchers studying visual perception and reading devised tests of rapid symbol, number, or object naming. Investigators later named these tests as RAN tasks and adapted them for studying concussion among other cognitive and visual pathologies. Several tests, including those for object and number naming, show capacity to distinguish athletes with concussions. As in the case of all performance-based measures, potential for learning effects should be considered when interpreting results. Further collection of baseline and postinjury data will help validate these RAN tasks as assessments of concussion by providing age-normative values, characterizing learning effects over repeat measurements, and establishing thresholds for clinically significant performance decrements. Furthermore, various RAN tasks are likely to be functionally distinct, engaging different neural networks according to the demands of each task. Investigators have turned to VOG as a method for collecting objective, precise data on ocular motor function in concussed individuals. VOG testing paradigms are flexible and often integrate various cognitive functions including executive functions such as task sequencing and switching, working and visuospatial memory, and attention. Several parameters of saccades, smooth pursuit eye movements, and more recently, disparity vergence are candidate Akhand et al: J Neuro-Ophthalmol 2019; 39: 68-81 vision-based markers for concussion. Adopting these assessments to a sideline environment remains a challenge, although several companies are now offering portable VOG-based assessments for head trauma. The cost, availability, and interpretation are just a few of the important issues that will have to be addressed before widespread use can be advocated. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: O. Akhand, S. L. Galetta, L. J. Balcer, and J. C. Rucker; b. Acquisition of data: O. Akhand, L. Hasanaj, J.-R. Rizzo, L. J. Balcer, and J. C. Rucker; c. Analysis and interpretation of data: O. Akhand, J.-R. Rizzo, L. 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