Eye Movement Research in the Twenty-First Century—a Window to the Brain, Mind, and More

Abstract

The study of eye movements not only addresses debilitating neuro-ophthalmological problems but has become an essential tool of basic neuroscience research. Eye movements are a classic way to evaluate brain function—traditionally in disorders affecting the brainstem and cerebellum. Abnormalities of eye movements have localizing value and help narrow the differential diagnosis of complex neurological problems. More recently, using sophisticated behavioral paradigms, measurement of eye movements has also been applied to disorders of the thalamus, basal ganglia, and cerebral cortex. Moreover, in contemporary neuroscience, eye movements play a key role in understanding cognition, behavior, and disorders of the mind. Examples include applications to higher-level decision-making processes as in neuroeconomics and psychiatric and cognitive disorders such as schizophrenia and autism. Eye movements have become valued as objective biomarkers to monitor the natural progression of disease and the effects of therapies. As specific genetic defects are identified for many neurological disorders, ocular motor function often becomes the cornerstone of phenotypic classification and differential diagnosis. Here, we introduce other important applications of eye movement research, including understanding movement disorders affecting the head and limbs. We also emphasize the need to develop standardized test batteries for eye movements of all types including the vestibulo-ocular responses. The evaluation and treatment of patients with cerebellar ataxia are particularly amenable to such an approach.

Eye movements are critical for the survival of any animal that sees. Promptly bringing an image to the fovea of an object that suddenly intrudes into one’s periphery, and then keeping the image stable on the fovea, allows the cognitive brain to analyze the visual scene in a tenth of a second. In this way, it can generate an immediate, and sometimes life or death, decision whether to flee, fight, embrace, or just do nothing. Neural correlates of eye movements are found in almost every corner of the brain, helping to provide the most reliable information from our visual systems for all aspects of behavior.

Using eye movements to understand human disease extends back to at least the mid-nineteenth century when early reports of strabismus [1,2,3,4,5] and nystagmus [4, 6,7,8,9,10,11,12,13] appeared. Nevertheless, in the years following, for almost another century, the literature on eye movements was meager. In the mid-1940s, however, the number of publications on nystagmus and strabismus began to grow (https://www.ncbi.nlm.nih.gov/pubmed/?term = nystagmus, https://www.ncbi.nlm.nih.gov/pubmed/?term = strabismus), and in the mid-1960s, there was another growth spurt with more studies reporting various types of dysfunction of eye movements in conditions affecting the brainstem or cerebellum. Topics such as adaptive control of eye movements and the central role of normal and abnormal vestibulo-ocular responses in revealing mechanisms underlying the control of eye movements of all types also began to receive special emphasis (Fig. 1) (https://www.ncbi.nlm.nih.gov/pubmed/?term=nystagmus, https://www.ncbi.nlm.nih.gov/pubmed/?term=strabismus, https://www.ncbi.nlm.nih.gov/pubmed/?term=eye+movement+brainstem, https://www.ncbi.nlm.nih.gov/pubmed/?term=eye+movement+ataxia, https://www.ncbi.nlm.nih.gov/pubmed/?term=eye+movement+motor+adaptation, https://www.ncbi.nlm.nih.gov/pubmed/?term=eye+movement+vestibulo-ocular+reflex).

Fig. 1
figure1

Number of publications normalized to their total in all years and corresponding year of publication. The normalization compares relative frequency of published literature on a given topic. In the mid-1940s, there was increase in publications about nystagmus and strabismus (arrow 1); in the mid-1960s, there was increase in publication frequency reporting cerebellar or brainstem eye movement deficits (arrow 2). Arrow 3 depicts the start of increasing numbers of publication on cognitive function and then a further increase in literature in this category (arrow 4). Today, there are more publications using eye movements to study cognitive function than all publications on eye movements and cerebellar ocular motor function

The 1960s became a watershed in ocular motor research for both technical and conceptual reasons. The magnetic field search coil method for measuring eye movements was a boon for ocular motor research in both humans and experimental animals. It gives accurate, sensitive, reliable measures of the position of the eye around all three axes of rotation. This methodology, combined with the new techniques of recording of activity from single neurons in alert behaving animals, made possible precise correlations between behavior and neural activity. New anatomical tracing techniques also helped to unravel the connectivity of the circuits that showed activity related to eye movements [14,15,16,17]. The effects of micro-injections of chemicals that mimic normal neurotransmitters, focal electrical stimulation, and naturally occurring experimental lesions in the brain improved our understanding of brain function [18,19,20,21,22,23,24,25,26,27,28,29,30,31]. Conceptually, bioengineering approaches, using systems analytical techniques, were combined with anatomical and physiological data, to develop biologically plausible models, replacing the “black box” approach to neural modeling. The involvement of bioengineers in eye movement research, exemplified by David A Robinson, enticed basic and clinical neuroscientists to adopt the “engineering approach” to understanding normal brain function and human disease [27, 32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47].

Beginning in the1960s, clinical ocular motor research largely focused on the disorders of the cerebellum, brainstem, and orbit. Key information came from studies of the physical properties of the “oculomotor plant,” the mechanical characteristics of the orbital contents that dictate what premotor commands were needed to move the eyes quickly to a new position and then to hold them there [48, 49]. Furthermore, largely based on studies in animals with experimental lesions and on patients with naturally occurring disorders of eye movements, the motor machinery in the brainstem and cerebellum that generated the requisite premotor commands was becoming relatively well understood. Consequently, eye movements became a powerful tool to measure motor function objectively in patients with neurological disorders and more generally as “a window to the workings of the brain.” There were several critical insights relating basic physiology and anatomy to behavior. They included (1) the concept of a neural network performing mathematical integration of eye velocity to eye position (neural integration) for steady gaze holding and (2) the use of internal models based on efference copy and internal feedback that enable the brain to predict and when necessary correct its motor commands. This capability functions both as part of immediate, on-line control of each individual movement and long-term adaptive control as part of motor learning and calibration. Note that many of these functions and concepts depend upon activity in the cerebellum, both directly and through its connections to the brainstem and higher-level structures.

More recently, eye movements have assumed another key role in neuroscience, as quantitative markers of higher-level aspects of behavior. Many studies that focus on cognitive and behavioral neuroscience—for example, reward, attention, planning, and prediction—and disorders, such as autism, schizophrenia, and neglect, use eye movements as a “read out” of what the brain is planning, mulling over, or excited about (Fig. 1) (https://www.ncbi.nlm.nih.gov/pubmed/?term=eye+movement+biomarker, https://www.ncbi.nlm.nih.gov/pubmed/?term=eye+movement+cognition, https://www.ncbi.nlm.nih.gov/pubmed/?term=eye+movement+autism, https://www.ncbi.nlm.nih.gov/pubmed/?term=eye+movement+cerebral+cortex, https://www.ncbi.nlm.nih.gov/pubmed/?term=eye+movement+psychology, https://www.ncbi.nlm.nih.gov/pubmed/?term=eye+movement+behavior). The slope of this growth in publications has increased even more in the last decade (Fig. 1). Not only the eyes are windows to the brain but they have become windows to the mind. As many new therapies for neurological and psychiatric diseases have emerged, eye movements have become the biomarker exemplar, easy to measure and easy to quantify (https://www.ncbi.nlm.nih.gov/pubmed/?term=eye+movement+biomarker). In the case of spinocerebellar ataxia type 6 (SCA6), for example, the amplitude of the vestibulo-ocular reflex (gain) is initially high due to a loss of the inhibition from Purkinje cells upon the vestibular nuclei but eventually, the gain becomes low as the disease progressively involves the vestibular nuclei in the brainstem.

The abrupt growth of the biomarker and behavioral literature using eye movements is also related to technical advances and, especially, the invention of portable, non-invasive, and cost-effective eye trackers. In the late 1900s, eye movement research required a cumbersome and costly infrastructure, and highly trained investigators for acquisition, analysis, and interpretation of eye movement data. In contrast, contemporary off-the-shelf systems neither require sophisticated expertise to establish an eye movement laboratory nor mandate extensive training in interpreting and analyzing the eye movement data. All information is available from preconfigured algorithms built into the manufacturer-provided software. Many of these systems are portable and easy to use at the bedside. Nevertheless, caution is required. All methods of recording and analyzing eye movements are susceptible to artifacts from the recording techniques themselves, from limitations in the computer analysis algorithms and unwanted fluctuations or noncompliance in the behavioral state of the subject or patient, which prevents them from properly performing the task.

What does this all mean to scientists and clinicians focusing on the function of the cerebellum and its diseases? We know more about the function of the cerebellum in the control of eye movements than on any other motor behavior. We know more about the anatomical substrate and compartmentalization within the cerebellum on eye movements than on any other motor behavior. We can record, quantify and interpret the effects of cerebellar lesions on eye movements better than on any other motor behavior. Taken together, eye movements become an ideal tool to probe both function and malfunction of the cerebellum. Consider saccades for example, inaccurate saccades—saccade dysmetria—is a hallmark feature of dysfunction of the dorsal cerebellar vermis and its underlying projection site, the posterior fastigial nucleus (saccade hypermetria) [30, 31, 50]. Other types of eye movements also show patterns of abnormality that localize to the cerebellum, gaze-evoked and downbeating nystagmus and impaired pursuit with the head still or moving point to the flocculus/paraflocculus, and periodic alternating nystagmus and impaired tilt suppression of post rotatory nystagmus to the nodulus [47]. Even finer distinctions can be made between the effects of lesions in small but adjacent structures within the cerebellum, for example, the flocculus versus the paraflocculus (tonsil) [18, 19, 26, 27, 29, 51, 52]. While not as well localized within the cerebellum, certain patterns of ocular misalignment strongly suggest cerebellar dysfunction (e.g., horizontal (eso, convergent) deviations of the eyes for distance viewing and vertical misalignment that alternates sense (which eye is higher) depending on right versus left gaze) [20, 53,54,55,56,57,58,59].

Similarly, eye movements and saccades in particular can be used to probe the functions of many other areas within the brain including within the thalamus, basal ganglia, and cerebral cortex. New behavioral paradigms have applications both in basic neuroscience research and many neurological and psychiatric disorders. They include (1) the antisaccade test (can the patient suppress a saccade to a target to a suddenly appearing in the visual periphery and instead generate a saccade to its opposite mirror location?), (2) the go no-go paradigm (when can the decision to make a saccade be revoked?), and (3) predictive tracking (can the patient anticipate the location of a target moving in a periodic fashion?). Inferring functions of the cerebellum based on behavior is particularly confounding because of the extensive interconnections and reciprocal influences between the cerebellum, brainstem, and the cerebral hemispheres. Nevertheless, carefully designed experiments using innovative testing paradigms can help tease out both normal and abnormal function. Novel imaging approaches too, anatomical, functional, and biochemical, paired with sophisticated behavior paradigms are boon to eye movement research. Using MRI spectroscopy, the performance during eye movement tasks can be correlated to the activity of specific neurotransmitters such as dopamine [60], GABA [61], or acetylcholine [62]. A combination of normal eye movement behavior with diffuse MRI-based tractography has revealed the cortical nodes associated with central activity related to motor programming needed to initiate movement [63]. Antisaccade performance in elderly patients has become a valuable predictor for their performance on executive function tasks [64]. In Parkinson’s disease, ocular motor behavior, quantitative volumetry of gray and white matters in the cerebral hemispheres, and executive function capabilities are well correlated [65]. There is a direct correlation between the latency for vertical antisaccades and atrophy of caudate, left inferior parietal lobule, and left frontal gyrus [66]. Transcranial magnetic stimulation (TMS), another high-temporal resolution technique, can interrupt saccades at different time points during their generation. Such studies can trace the flow of information through different parts of the brain from activation by a stimulus to the programming of the movement to the execution of the saccade itself [67,68,69].

What is needed now? Perhaps first is that neurologists become more aware of how eye movements can be used in their clinics, for diagnosis, monitoring of therapies, and clinical and basic research. A careful clinical bedside evaluation, using only visual inspection, of each of the major subtypes of eye movements—saccades, pursuit, gaze holding, vestibular responses, and alignment and vergence—takes only a few minutes and provides much useful information toward accurate diagnosis. Specific patterns of abnormalities often provide key localizing information. When eye movements are used as biomarkers or for basic research, quantitative recording techniques become necessary. Another critical goal is to develop and validate standardized testing batteries among laboratories [70]. A key aspect of cerebellar motor control, infrequently used as a biomarker, is the ability to undergo ocular motor adaptation, a core function of what David Robinson called “the cerebellar repair shop.” As we make progress in the pharmacotherapy of neurodegenerative conditions and disease-modifying agents in the twenty-first century, it will become increasingly critical to define biomarkers that can track the evolution of cerebellar function. The eye movements can be precise and quantitative biomarkers to measure the effects of the novel pharmacotherapy on the cerebellar function. The motor tasks such as saccades, pursuit, gaze holding, vestibular ocular reflex, and vestibular ocular reflex cancelation can be objective biomarkers to measure the effects of pharmacotherapy on cerebellar motor function. Measure of cerebellar motor learning using saccade adaptation, pursuit adaptation, and vestibular ocular reflex adaptation can quantify the effects of pharmacotherapy on early or preclinical cerebellar disorders. Saccade adaptation occurs over short and long timescales. Cerebellar deficit results in impairment in shorter timescale while olivo-cerebellar dysfunction affects both timescales [71, 72]. Effects of pharmacotherapy on saccade adaptation task will be able to distinctly identify the cerebellar influence. Finally, non-motor ocular motor tests, such as antisaccade, memory-guided saccades, and go no-go task may allow objective measure of pharmacotherapy on the non-motor domain of the cerebellar function.

Currently, there are limited options for the pharmacotherapy of nystagmus and other gaze holding disorders. Classic literature has suggested baclofen as a treatment of cerebellar nystagmus, primarily the downbeat and periodic alternating nystagmus [73,74,75]. Recent studies have shown the efficacy of the aminopyridines in the treatment of cerebellar nystagmus [75,76,77,78,79]. NMDA receptor antagonists such as memantine and alpha-2-delta calcium channel blocker such as gabapentin have been useful to treat the pendular nystagmus due to olivo-cerebellar dysfunction in the syndrome of ocular palatal tremor and that due of demyelinating disorders [80]. Contemporary studies have identified the role of ion channels in the pathogenesis of nystagmus and saccadic oscillations [80,81,82]. Therefore, it is critical to consider selective ion channel blockers as therapeutic options for the treatment of cerebellar nystagmus [81, 83].

Finally, the successful “ocular motor approach” can be applied to other types of disordered movement as tremor and cervical dystonia. For example, the concept of neural integration for holding the eyes still can be applied to the complex head movement patterns in a cervical dystonia, and to holding other parts of the body still also [84, 85]. In the ocular motor system, the abnormal function of the neural integrator leads to centripetal drifts of the eyes with consequent gaze-evoked nystagmus. Similar dysfunction of a head movement neural integrator leads to jerky head oscillations typical of cervical dystonia. Malfunction of a head neural integrator, due to impaired cerebellar, basal ganglia, or peripheral feedback [85], is analogous to ideas about abnormal feedback and the ocular motor integrator. The neural circuits controlling saccades and those controlling ballistic limb movements show many analogies. An example is applying the ideas underlying neuromimetic, ion channel-based models of saccadic oscillations to the hand oscillations (e.g., essential tremor) [81]. Such conductance-based models also suggest a physiological rationale for drugs used to treat essential tremor.

In summary, there are many reasons to study eye movements (Table 1). Eye movements are a common interface among scientific investigations by physicians, psychologists, biologists, biomedical engineers, rehabilitation specialists, and pharmacologists. Eye movements have been used to investigate function in humans, non-human primates, canines, rodents, and fish. They are easy to measure, quantify, and analyze; easy to manipulate in sophisticated behavioral paradigms; and can be subject to different types of transcranial stimulation. Finally, the study of eye movements is at the forefront of translational research. Eye movement studies in patients have led to fundamental discoveries of how the brain works, and conversely, the results of basic studies of the physiology of eye movements can be applied directly to the bedside for better treatment and diagnosis. It is not an exaggeration to say that the future is bright for all those interested in using eye movements to study how the brain works and how to better diagnose and treat our patients.

Table 1 Why should we study eye movements?

References

  1. 1.

    Walsh TW. On the treatment of strabismus. Prov Med Surg J. 1840;1(3):38–9.

    CAS  Google Scholar 

  2. 2.

    Estlin JB. Report on the results of one hundred operations for strabismus. Prov Med J Retrosp Med Sci. 1842;4(95):303–6.

    PubMed  PubMed Central  CAS  Google Scholar 

  3. 3.

    Agnew CR. A contribution to the subject of strabismus. Trans Am Ophthalmol Soc. 1870;1(7):148–51.

    PubMed  PubMed Central  CAS  Google Scholar 

  4. 4.

    Pomeroy OD. A case of nystagmus, associated with concomitant convergent strabismus, in emmetropic eyes, relieved by correction of the squint. Trans Am Ophthalmol Soc. 1875;2:283.

    PubMed  PubMed Central  CAS  Google Scholar 

  5. 5.

    Hirschberg J. The quantitative analysis of diplopic strabismus. Br Med J. 1881;1(1044):5–9. https://doi.org/10.1136/bmj.1.1044.5.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. 6.

    Hakas P, Kornhuber HH. Vestibular nystagmus in cerebral lesions in man. Arch Psychiatr Nervenkr Z Gesamte Neurol Psychiatr. 1959;200(1):19–35. https://doi.org/10.1007/BF00361353.

    Article  PubMed  CAS  Google Scholar 

  7. 7.

    Kornhuber HH. Periodic alternating nystagmus (nystagmus alternans) and excitability of the vestibular system. Arch Ohren Nasen Kehlkopfheilkd. 1959;174(3):182–209. https://doi.org/10.1007/BF02103181.

    Article  PubMed  CAS  Google Scholar 

  8. 8.

    Lange G, Kornhuber HH. On the importance of peripheral and central vestibular disorders after head traumas. Electronystagmographic-statistical studies. Arch Ohren Nasen Kehlkopfheilkd. 1962;179(4):366–85. https://doi.org/10.1007/BF02103689.

    Article  PubMed  CAS  Google Scholar 

  9. 9.

    Dichgans J, Kornhuber HH. A rare type of hereditary nystagmus with autosomal-dominant inheritance and special phenomenon: vertical nystagmus component and disorder of the vertical and horizontal optokinetic nystagmus. Acta Genet Stat Med. 1964;14:240–50.

    PubMed  CAS  Google Scholar 

  10. 10.

    Potthoff PC, Purckhauer K, Kornhuber HH. Nystagmography, diagnosis and course of cerebellopontile angle tumors. Dtsch Z Nervenheilkd. 1965;187(5):497–502. https://doi.org/10.1007/BF00244368.

    Article  PubMed  CAS  Google Scholar 

  11. 11.

    Kornhuber HH. On frequent, but rarely observed forms of nystagmus and vertigo: paroxysmal positional vertigo and latent fixation nystagmus. Nervenarzt. 1965;36(8):361–2.

    PubMed  CAS  Google Scholar 

  12. 12.

    Frenzel H. Topographic plan of the nystagmogenic vestibular complex. Arch Ohren Nasen Kehlkopfheilkd. 1956;168(4):269–78.

    Article  PubMed  CAS  Google Scholar 

  13. 13.

    Frenzel H, Tonndorf EE. Nystagmus mobilization with closed eyes and in the darkness and elimination of fixation by spectacles with a lighting device. Pract Otorhinolaryngol (Basel). 1957;19(6):507–17.

    CAS  Google Scholar 

  14. 14.

    Voogd J. The efferent connections in the cat cerebellum. Ned Tijdschr Geneeskd. 1960;104:2444.

    PubMed  CAS  Google Scholar 

  15. 15.

    Voogd J. Comparative aspects of the structure and fibre connexions of the mammalian cerebellum. Prog Brain Res. 1967;25:94–134. https://doi.org/10.1016/S0079-6123(08)60963-2.

    Article  PubMed  CAS  Google Scholar 

  16. 16.

    Voogd J, Broere G, van Rossum J. The medio-lateral distribution of the spinocerebellar projection in the anterior lobe and the simple lobule in the cat and a comparison with some other afferent fibre systems. Psychiatr Neurol Neurochir. 1969;72(1):137–51.

    PubMed  CAS  Google Scholar 

  17. 17.

    Voogd J. Bolk’s subdivision of the mammalian cerebellum. Growth centres and functional zones. Acta Morphol Neerl Scand. 1975;13(1–2):35–54.

    PubMed  CAS  Google Scholar 

  18. 18.

    Yamazaki A, Zee DS. Rebound nystagmus: EOG analysis of a case with a floccular tumour. Br J Ophthalmol. 1979;63(11):782–6. https://doi.org/10.1136/bjo.63.11.782.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. 19.

    Zee DS, Yamazaki A, Butler PH, Gucer G. Effects of ablation of flocculus and paraflocculus of eye movements in primate. J Neurophysiol. 1981;46(4):878–99. https://doi.org/10.1152/jn.1981.46.4.878.

    Article  PubMed  CAS  Google Scholar 

  20. 20.

    Takagi M, Tamargo R, Zee DS. Effects of lesions of the cerebellar oculomotor vermis on eye movements in primate: binocular control. Prog Brain Res. 2003;142:19–33. https://doi.org/10.1016/S0079-6123(03)42004-9.

    Article  PubMed  Google Scholar 

  21. 21.

    Tokumasu K, Goto K, Cohen B. Eye movements from vestibular nuclei stimulation in monkeys. Ann Otol Rhinol Laryngol. 1969;78(5):1105–19. https://doi.org/10.1177/000348946907800516.

    Article  PubMed  CAS  Google Scholar 

  22. 22.

    Komatsuzaki A, Harris HE, Alpert J, Cohen B. Horizontal nystagmus of rhesus monkeys. Acta Otolaryngol. 1969;67(5):535–51. https://doi.org/10.3109/00016486909125481.

    Article  PubMed  CAS  Google Scholar 

  23. 23.

    Cohen B, Uemura T, Takemori S. Effects of labyrinthectomy on optokinetic nystagmus (OKN) and optokinetic after-nystagmus (OKAN). Int J Equilib Res. 1973;3(1):88–93.

    PubMed  CAS  Google Scholar 

  24. 24.

    Uemura T, Cohen B. Effects of vestibular nuclei lesions on vestibulo-ocular reflexes and posture in monkeys. Acta Otolaryngol Suppl. 1973;315:1–71.

    PubMed  CAS  Google Scholar 

  25. 25.

    Takemori S, Cohen B. Visual suppression of vestibular nystagmus in rhesus monkeys. Brain Res. 1974;72(2):203–12. https://doi.org/10.1016/0006-8993(74)90859-2.

    Article  PubMed  CAS  Google Scholar 

  26. 26.

    Takemori S, Cohen B. Loss of visual suppression of vestibular nystagmus after flocculus lesions. Brain Res. 1974;72(2):213–24. https://doi.org/10.1016/0006-8993(74)90860-9.

    Article  PubMed  CAS  Google Scholar 

  27. 27.

    Waespe W, Cohen B, Raphan T. Role of the flocculus and paraflocculus in optokinetic nystagmus and visual-vestibular interactions: effects of lesions. Exp Brain Res. 1983;50(1):9–33.

    Article  PubMed  CAS  Google Scholar 

  28. 28.

    Waespe W, Cohen B, Raphan T. Effects of flocculectomy on vestibular and optokinetic nystagmus and unit activity in the vestibular nuclei. Adv Otorhinolaryngol. 1983;30:226–9.

    PubMed  CAS  Google Scholar 

  29. 29.

    Waespe W, Cohen B. Flocculectomy and unit activity in the vestibular nuclei during visual-vestibular interactions. Exp Brain Res. 1983;51(1):23–35.

    Article  PubMed  CAS  Google Scholar 

  30. 30.

    Robinson FR, Straube A, Fuchs AF. Role of the caudal fastigial nucleus in saccade generation. II. Effects of muscimol inactivation. J Neurophysiol. 1993;70(5):1741–58. https://doi.org/10.1152/jn.1993.70.5.1741.

    Article  PubMed  CAS  Google Scholar 

  31. 31.

    Straube A, Helmchen C, Robinson F, Fuchs A, Buttner U. Saccadic dysmetria is similar in patients with a lateral medullary lesion and in monkeys with a lesion of the deep cerebellar nucleus. J Vestib Res. 1994;4(5):327–33.

    PubMed  CAS  Google Scholar 

  32. 32.

    Robinson DA. A method of measuring eye movement using a scleral search coil in a magnetic field. IEEE Trans Biomed Eng. 1963;10:137–45.

    PubMed  CAS  Google Scholar 

  33. 33.

    Robinson DA. The mechanics of human saccadic eye movement. J Physiol. 1964;174(2):245–64. https://doi.org/10.1113/jphysiol.1964.sp007485.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. 34.

    Robinson DA. The measurement of eye movement using magnetic induction in a contact lens coil. Biomed Sci Instrum. 1964;2:97–106.

    PubMed  CAS  Google Scholar 

  35. 35.

    Fuchs AF, Robinson DA. A method for measuring horizontal and vertical eye movement chronically in the monkey. J Appl Physiol. 1966;21(3):1068–70. https://doi.org/10.1152/jappl.1966.21.3.1068.

    Article  PubMed  CAS  Google Scholar 

  36. 36.

    Robinson DA. Eye movement control in primates. The oculomotor system contains specialized subsystems for acquiring and tracking visual targets. Science. 1968;161(3847):1219–24. https://doi.org/10.1126/science.161.3847.1219.

    Article  PubMed  CAS  Google Scholar 

  37. 37.

    Robinson DA. A note on the oculomotor pathway. Exp Neurol. 1968;22(1):130–2. https://doi.org/10.1016/0014-4886(68)90024-1.

    Article  PubMed  CAS  Google Scholar 

  38. 38.

    Zee DS, Friendlich AR, Robinson DA. The mechanism of downbeat nystagmus. Arch Neurol. 1974;30(3):227–37. https://doi.org/10.1001/archneur.1974.00490330035006.

    Article  PubMed  CAS  Google Scholar 

  39. 39.

    Zee DS, Yee RD, Cogan DG, Robinson DA, Engel WK. Ocular motor abnormalities in hereditary cerebellar ataxia. Brain. 1976;99(2):207–34. https://doi.org/10.1093/brain/99.2.207.

    Article  PubMed  CAS  Google Scholar 

  40. 40.

    Zee DS, Optican LM, Cook JD, Robinson DA, Engel WK. Slow saccades in spinocerebellar degeneration. Arch Neurol. 1976;33(4):243–51. https://doi.org/10.1001/archneur.1976.00500040027004.

    Article  PubMed  CAS  Google Scholar 

  41. 41.

    Zee DS, Robinson DA. A hypothetical explanation of saccadic oscillations. Ann Neurol. 1979;5(5):405–14. https://doi.org/10.1002/ana.410050502.

    Article  PubMed  CAS  Google Scholar 

  42. 42.

    Leigh RJ, Robinson DA, Zee DS. A hypothetical explanation for periodic alternating nystagmus: instability in the optokinetic-vestibular system. Ann N Y Acad Sci. 1981;374(1 Vestibular an):619–35. https://doi.org/10.1111/j.1749-6632.1981.tb30906.x.

    Article  PubMed  CAS  Google Scholar 

  43. 43.

    Becker W, Fuchs AF. Further properties of the human saccadic system: eye movements and correction saccades with and without visual fixation points. Vis Res. 1969;9(10):1247–58. https://doi.org/10.1016/0042-6989(69)90112-6.

    Article  PubMed  CAS  Google Scholar 

  44. 44.

    Fuchs AF, Luschei ES. Firing patterns of abducens neurons of alert monkeys in relationship to horizontal eye movement. J Neurophysiol. 1970;33(3):382–92. https://doi.org/10.1152/jn.1970.33.3.382.

    Article  PubMed  CAS  Google Scholar 

  45. 45.

    Fuchs AF, Luschei ES. Unit activity in the brainstem related to eye movement. Possible inputs to the motor nuclei. Bibl Ophthalmol. 1972;82:17–27.

    PubMed  CAS  Google Scholar 

  46. 46.

    Fuchs AF, Kimm J. Unit activity in vestibular nucleus of the alert monkey during horizontal angular acceleration and eye movement. J Neurophysiol. 1975;38(5):1140–61. https://doi.org/10.1152/jn.1975.38.5.1140.

    Article  PubMed  CAS  Google Scholar 

  47. 47.

    Raphan T, Matsuo V, Cohen B. Velocity storage in the vestibulo-ocular reflex arc (VOR). Exp Brain Res. 1979;35(2):229–48.

    Article  PubMed  CAS  Google Scholar 

  48. 48.

    Robinson DA, O'Meara DM, Scott AB, Collins CC. Mechanical components of human eye movements. J Appl Physiol. 1969;26(5):548–53. https://doi.org/10.1152/jappl.1969.26.5.548.

    Article  PubMed  CAS  Google Scholar 

  49. 49.

    Robinson DA. A quantitative analysis of extraocular muscle cooperation and squint. Investig Ophthalmol. 1975;14(11):801–25.

    CAS  Google Scholar 

  50. 50.

    Botzel K, Rottach K, Buttner U. Normal and pathological saccadic dysmetria. Brain. 1993;116(Pt 2):337–53. https://doi.org/10.1093/brain/116.2.337.

    Article  PubMed  Google Scholar 

  51. 51.

    Lisberger SG, Miles FA, Zee DS. Signals used to compute errors in monkey vestibuloocular reflex: possible role of flocculus. J Neurophysiol. 1984;52(6):1140–53. https://doi.org/10.1152/jn.1984.52.6.1140.

    Article  PubMed  CAS  Google Scholar 

  52. 52.

    Versino M, Hurko O, Zee DS. Disorders of binocular control of eye movements in patients with cerebellar dysfunction. Brain. 1996;119(Pt 6):1933–50. https://doi.org/10.1093/brain/119.6.1933.

    Article  PubMed  Google Scholar 

  53. 53.

    Kono R, Hasebe S, Ohtsuki H, Kashihara K, Shiro Y. Impaired vertical phoria adaptation in patients with cerebellar dysfunction. Invest Ophthalmol Vis Sci. 2002;43(3):673–8.

    PubMed  Google Scholar 

  54. 54.

    Wong AM, Sharpe JA. Cerebellar skew deviation and the torsional vestibuloocular reflex. Neurology. 2005;65(3):412–9. https://doi.org/10.1212/01.wnl.0000171860.02355.61.

    Article  PubMed  Google Scholar 

  55. 55.

    Chandrakumar M, Blakeman A, Goltz HC, Sharpe JA, Wong AM. Static ocular counterroll reflex in skew deviation. Neurology. 2011;77(7):638–44. https://doi.org/10.1212/WNL.0b013e3182299f71.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. 56.

    Joshi AC, Das VE. Muscimol inactivation of caudal fastigial nucleus and posterior interposed nucleus in monkeys with strabismus. J Neurophysiol. 2013;110(8):1882–91. https://doi.org/10.1152/jn.00233.2013.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. 57.

    Ghasia FF, Gulati D, Westbrook EL, Shaikh AG. Viewing condition dependence of the gaze-evoked nystagmus in Arnold Chiari type 1 malformation. J Neurol Sci. 2014;339(1–2):134–9. https://doi.org/10.1016/j.jns.2014.01.045.

    Article  PubMed  Google Scholar 

  58. 58.

    Shaikh AG, Ghasia FF. Neuro-ophthalmology of type 1 Chiari malformation. Expert Rev Ophthalmol. 2015;10(4):351–7. https://doi.org/10.1586/17469899.2015.1057505.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. 59.

    Ghasia FF, Wilmot G, Ahmed A, Shaikh AG. Strabismus and micro-opsoclonus in Machado-Joseph disease. Cerebellum. 2016;15(4):491–7. https://doi.org/10.1007/s12311-015-0718-0.

    Article  PubMed  Google Scholar 

  60. 60.

    Sawaguchi T, Goldman-Rakic PS. The role of D1-dopamine receptor in working memory: local injections of dopamine antagonists into the prefrontal cortex of rhesus monkeys performing an oculomotor delayed-response task. J Neurophysiol. 1994;71(2):515–28. https://doi.org/10.1152/jn.1994.71.2.515.

    Article  PubMed  CAS  Google Scholar 

  61. 61.

    Sumner P, Edden RA, Bompas A, Evans CJ, Singh KD. More GABA, less distraction: a neurochemical predictor of motor decision speed. Nat Neurosci. 2010;13(7):825–7. https://doi.org/10.1038/nn.2559.

    Article  PubMed  CAS  Google Scholar 

  62. 62.

    Kobayashi Y, Saito Y, Isa T. Facilitation of saccade initiation by brainstem cholinergic system. Brain and Development. 2001;23(Suppl 1):S24–7. https://doi.org/10.1016/S0387-7604(01)00330-8.

    Article  PubMed  Google Scholar 

  63. 63.

    Anderson EJ, Jones DK, O'Gorman RL, Leemans A, Catani M, Husain M. Cortical network for gaze control in humans revealed using multimodal MRI. Cereb Cortex. 2012;22(4):765–75. https://doi.org/10.1093/cercor/bhr110.

    Article  PubMed  Google Scholar 

  64. 64.

    Mirsky JB, Heuer HW, Jafari A, Kramer JH, Schenk AK, Viskontas IV, et al. Anti-saccade performance predicts executive function and brain structure in normal elders. Cogn Behav Neurol. 2011;24(2):50–8. https://doi.org/10.1097/WNN.0b013e318223f6c6.

    Article  PubMed  PubMed Central  Google Scholar 

  65. 65.

    Perneczky R, Ghosh BC, Hughes L, Carpenter RH, Barker RA, Rowe JB. Saccadic latency in Parkinson’s disease correlates with executive function and brain atrophy, but not motor severity. Neurobiol Dis. 2011;43(1):79–85. https://doi.org/10.1016/j.nbd.2011.01.032.

    Article  PubMed  PubMed Central  Google Scholar 

  66. 66.

    Rupp J, Dzemidzic M, Blekher T, West J, Hui S, Wojcieszek J, et al. Comparison of vertical and horizontal saccade measures and their relation to gray matter changes in premanifest and manifest Huntington disease. J Neurol. 2012;259(2):267–76. https://doi.org/10.1007/s00415-011-6172-0.

    Article  PubMed  Google Scholar 

  67. 67.

    Xu-Wilson M, Tian J, Shadmehr R, Zee DS. TMS perturbs saccade trajectories and unmasks an internal feedback controller for saccades. J Neurosci. 2011;31(32):11537–46. https://doi.org/10.1523/JNEUROSCI.1584-11.2011.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  68. 68.

    Vernet M, Yang Q, Kapoula Z. Guiding binocular saccades during reading: a TMS study of the PPC. Front Hum Neurosci. 2011;5:14.

    Article  PubMed  PubMed Central  Google Scholar 

  69. 69.

    Yang Q, Kapoula Z. Distinct control of initiation and metrics of memory-guided saccades and vergence by the FEF: a TMS study. PLoS One. 2011;6(5):e20322. https://doi.org/10.1371/journal.pone.0020322.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  70. 70.

    Antoniades C, Ettinger U, Gaymard B, Gilchrist I, Kristjansson A, Kennard C, et al. An internationally standardised antisaccade protocol. Vis Res. 2013;84:1–5. https://doi.org/10.1016/j.visres.2013.02.007.

    Article  PubMed  Google Scholar 

  71. 71.

    Shaikh AG, Wong AL, Optican LM, Zee DS. Impaired motor learning in a disorder of the inferior olive: is the cerebellum confused? Cerebellum. 2017;16(1):158–67. https://doi.org/10.1007/s12311-016-0785-x.

    Article  PubMed  PubMed Central  Google Scholar 

  72. 72.

    Xu-Wilson M, Chen-Harris H, Zee DS, Shadmehr R. Cerebellar contributions to adaptive control of saccades in humans. J Neurosci. 2009;29(41):12930–9. https://doi.org/10.1523/JNEUROSCI.3115-09.2009.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  73. 73.

    Halmagyi GM, Rudge P, Gresty MA, Leigh RJ, Zee DS. Treatment of periodic alternating nystagmus. Ann Neurol. 1980;8(6):609–11. https://doi.org/10.1002/ana.410080611.

    Article  PubMed  CAS  Google Scholar 

  74. 74.

    Averbuch-Heller L, Tusa RJ, Fuhry L, Rottach KG, Ganser GL, Heide W, et al. A double-blind controlled study of gabapentin and baclofen as treatment for acquired nystagmus. Ann Neurol. 1997;41(6):818–25. https://doi.org/10.1002/ana.410410620.

    Article  PubMed  CAS  Google Scholar 

  75. 75.

    Strupp M, Thurtell MJ, Shaikh AG, Brandt T, Zee DS, Leigh RJ. Pharmacotherapy of vestibular and ocular motor disorders, including nystagmus. J Neurol. 2011;258(7):1207–22. https://doi.org/10.1007/s00415-011-5999-8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  76. 76.

    Strupp M, Kalla R, Glasauer S, Wagner J, Hufner K, Jahn K, et al. Aminopyridines for the treatment of cerebellar and ocular motor disorders. Prog Brain Res. 2008;171:535–41. https://doi.org/10.1016/S0079-6123(08)00676-6.

    Article  PubMed  Google Scholar 

  77. 77.

    Shaikh AG, Marti S, Tarnutzer AA, Palla A, Crawford TO, Zee DS, et al. Effects of 4-aminopyridine on nystagmus and vestibulo-ocular reflex in ataxia-telangiectasia. J Neurol. 2013;260(11):2728–35. https://doi.org/10.1007/s00415-013-7046-4.

    Article  PubMed  CAS  Google Scholar 

  78. 78.

    Shaikh AG. Does 4-aminopyridine “beat” downbeat nystagmus? J Neurol Neurosurg Psychiatry. 2013;84(12):1298–9. https://doi.org/10.1136/jnnp-2013-305191.

    Article  PubMed  Google Scholar 

  79. 79.

    Shaikh AG, Palla A, Marti S, Olasagasti I, Optican LM, Zee DS, et al. Role of cerebellum in motion perception and vestibulo-ocular reflex-similarities and disparities. Cerebellum. 2013;12(1):97–107. https://doi.org/10.1007/s12311-012-0401-7.

    Article  PubMed  PubMed Central  Google Scholar 

  80. 80.

    Shaikh AG, Thurtell MJ, Optican LM, Leigh RJ. Pharmacological tests of hypotheses for acquired pendular nystagmus. Ann N Y Acad Sci. 2011;1233(1):320–6. https://doi.org/10.1111/j.1749-6632.2011.06118.x.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  81. 81.

    Shaikh AG, Miura K, Optican LM, Ramat S, Leigh RJ, Zee DS. A new familial disease of saccadic oscillations and limb tremor provides clues to mechanisms of common tremor disorders. Brain. 2007;130(Pt 11):3020–31. https://doi.org/10.1093/brain/awm240.

    Article  PubMed  Google Scholar 

  82. 82.

    Shaikh AG, Hong S, Liao K, Tian J, Solomon D, Zee DS, et al. Oculopalatal tremor explained by a model of inferior olivary hypertrophy and cerebellar plasticity. Brain. 2010;133(Pt 3):923–40. https://doi.org/10.1093/brain/awp323.

    Article  PubMed  PubMed Central  Google Scholar 

  83. 83.

    Shaikh AG, Zee DS, Optican LM, Miura K, Ramat S, Leigh RJ. The effects of ion channel blockers validate the conductance-based model of saccadic oscillations. Ann N Y Acad Sci. 2011;1233(1):58–63. https://doi.org/10.1111/j.1749-6632.2011.06130.x.

    Article  PubMed  PubMed Central  Google Scholar 

  84. 84.

    Shadmehr R. Distinct neural circuits for control of movement vs. holding still. J Neurophysiol. 2017;117(4):1431–60. https://doi.org/10.1152/jn.00840.2016.

    Article  PubMed  PubMed Central  Google Scholar 

  85. 85.

    Shaikh AG, Zee DS, Crawford JD, Jinnah HA. Cervical dystonia: a neural integrator disorder. Brain. 2016;139(Pt 10):2590–9. https://doi.org/10.1093/brain/aww141.

    Article  PubMed  PubMed Central  Google Scholar 

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Funding

AS is supported by Dystonia Coalition and Dystonia Medical Research Foundation career development award.

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Correspondence to Aasef G. Shaikh.

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Shaikh, A.G., Zee, D.S. Eye Movement Research in the Twenty-First Century—a Window to the Brain, Mind, and More. Cerebellum 17, 252–258 (2018). https://doi.org/10.1007/s12311-017-0910-5

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Keywords

  • Saccade
  • Vestibulo-ocular reflex
  • Pursuit