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1.  Saccadic Palsy following Cardiac Surgery: Possible Role of Perineuronal Nets 
PLoS ONE  2015;10(7):e0132075.
Perineuronal nets (PN) form a specialized extracellular matrix around certain highly active neurons within the central nervous system and may help to stabilize synaptic contacts, promote local ion homeostasis, or play a protective role. Within the ocular motor system, excitatory burst neurons and omnipause neurons are highly active cells that generate rapid eye movements – saccades; both groups of neurons contain the calcium-binding protein parvalbumin and are ensheathed by PN. Experimental lesions of excitatory burst neurons and omnipause neurons cause slowing or complete loss of saccades. Selective palsy of saccades in humans is reported following cardiac surgery, but such cases have shown normal brainstem neuroimaging, with only one clinicopathological study that demonstrated paramedian pontine infarction. Our objective was to test the hypothesis that lesions of PN surrounding these brainstem saccade-related neurons may cause saccadic palsy.
Together with four controls we studied the brain of a patient who had developed a permanent selective saccadic palsy following cardiac surgery and died several years later. Sections of formalin-fixed paraffin-embedded brainstem blocks were applied to double-immunoperoxidase staining of parvalbumin and three different components of PN. Triple immunofluorescence labeling for all PN components served as internal controls. Combined immunostaining of parvalbumin and synaptophysin revealed the presence of synapses.
Excitatory burst neurons and omnipause neurons were preserved and still received synaptic input, but their surrounding PN showed severe loss or fragmentation.
Our findings support current models and experimental studies of the brainstem saccade-generating neurons and indicate that damage to PN may permanently impair the function of these neurons that the PN ensheathe. How a postulated hypoxic mechanism could selectively damage the PN remains unclear. We propose that the well-studied saccadic eye movement system provides an accessible model to evaluate the role of PN in health and disease.
PMCID: PMC4489868  PMID: 26135580
2.  Simultaneous Recordings of Human Microsaccades and Drifts with a Contemporary Video Eye Tracker and the Search Coil Technique 
PLoS ONE  2015;10(6):e0128428.
Human eyes move continuously, even during visual fixation. These “fixational eye movements” (FEMs) include microsaccades, intersaccadic drift and oculomotor tremor. Research in human FEMs has grown considerably in the last decade, facilitated by the manufacture of noninvasive, high-resolution/speed video-oculography eye trackers. Due to the small magnitude of FEMs, obtaining reliable data can be challenging, however, and depends critically on the sensitivity and precision of the eye tracking system. Yet, no study has conducted an in-depth comparison of human FEM recordings obtained with the search coil (considered the gold standard for measuring microsaccades and drift) and with contemporary, state-of-the art video trackers. Here we measured human microsaccades and drift simultaneously with the search coil and a popular state-of-the-art video tracker. We found that 95% of microsaccades detected with the search coil were also detected with the video tracker, and 95% of microsaccades detected with video tracking were also detected with the search coil, indicating substantial agreement between the two systems. Peak/mean velocities and main sequence slopes of microsaccades detected with video tracking were significantly higher than those of the same microsaccades detected with the search coil, however. Ocular drift was significantly correlated between the two systems, but drift speeds were higher with video tracking than with the search coil. Overall, our combined results suggest that contemporary video tracking now approaches the search coil for measuring FEMs.
PMCID: PMC4452707  PMID: 26035820
3.  Critical role of cerebellar fastigial nucleus in programming sequences of saccades 
The cerebellum plays an important role in programming accurate saccades. Cerebellar lesions affecting the ocular motor region of the fastigial nucleus (FOR) cause saccadic hypermetria; however, if a second target is presented before a saccade can be initiated (double-step paradigm), saccade hypermetria may be decreased. We tested the hypothesis that the cerebellum, especially FOR, plays a pivotal role in programming sequences of saccades. We studied patients with saccadic hypermetria due either to genetic cerebellar ataxia or surgical lesions affecting FOR and confirmed that the gain of initial saccades made to double-step stimuli was reduced compared with the gain of saccades to single target jumps. Based on measurements of the intersaccadic interval, we found that the ability to perform parallel processing of saccades was reduced or absent in all of our patients with cerebellar disease. Our results support the crucial role of the cerebellum, especially FOR, in programming sequences of saccades.
PMCID: PMC3187558  PMID: 21950988
fastigial nucleus; double-step; saccade; latency; spinocerebellar ataxia; hypermetria; parallel processing
4.  Influence of orbital eye position on vertical saccades in progressive supranuclear palsy 
Disturbance of vertical saccadesis a cardinal feature of progressive supranuclear palsy (PSP). We investigated whether the amplitude and peak velocity of saccades is affected by the orbital position fromwhich movements start in PSP patients and age-matched control subjects. Subjects made vertical saccades in response to ± 5 degree vertical target jumps with their heads in one of three positions: head “center,” head pitched forward ~15 degrees, and head pitched back ~ 15 degrees.All patients showed some effect of starting eye position, whether beginning in the upward or downward field of gaze, on saccade amplitude, peak velocity (PV), and net range of movement. Generally, reduction of amplitude and PV were commensurate and bidirectional in the affected hemifield of gaze. Such findings are unlikelyto be due to orbital factors and could be explained by varying degrees of involvement of rostral midbrain nucleiin the pathological process.
PMCID: PMC3187876  PMID: 21950977
saccades; midbrain; neural integrator; eyeball; parkinsonian disorders
5.  Effects of Cerebellar Disease on Sequences of Rapid Eye Movements 
Vision research  2011;51(9):1064-1074.
Studying saccades can illuminate the more complex decision-making processes required for everyday movements. The double-step task, in which a target jumps to two successive locations before the subject has time to react, has proven a powerful research tool to investigate the brain’s ability to program sequential responses. We asked how patients with a range of cerebellar disorders responded to the double-step task, specifically, whether the initial saccadic response made to a target is affected by the appearance of a second target jump. We also sought to determine whether cerebellar patients were able to make corrective saccades towards the remembered second target location, if it were turned off soon after presentation. We tested saccades to randomly interleaved single- and double-step target jumps to eight locations on a circle. Patient’s initial responses to double-step stimuli showed 50% more error than saccades to single target jumps, and often, they failed to make a saccade to the first target jump. The presence of a second target jump had similar, but smaller effects in control subjects (error increased by 18%). During memory-guided double-step trials, both patients and controls made corrective saccades in darkness to the remembered location of the second jump. We conclude that in cerebellar patients, the second target jump interferes with programming of the saccade to the first target jump of a double-step stimulus; this defect highlights patients’ impaired ability to respond appropriately to sudden, conflicting changes in their environment. Conversely, since cerebellar patients can make corrective memory-guided saccades in darkness, they retain the ability to remember spatial locations, possibly due to non-retinal neural signals (corollary discharge) from cerebral hemispheric areas concerned with spatial localization.
PMCID: PMC3084368  PMID: 21385592
Saccades; double-step; dysmetria; cerebellum, fastigial nucleus; efference copy
6.  Changes in Dynamic and Kinematic Properties of Saccades in Ocular Myasthenia following Intravenous Immunoglobulin Treatment 
We studied the dynamics and kinematics of saccades in a patient with severe ocular myasthenia before and after treatment with intravenous immunoglobulin (IVIG). Before therapy, horizontal saccades were hypometric, but faster than similar-sized saccades made by normal subjects. During a 5-minute test period, saccades decreased in size (fatigue effect), but remained faster than those of controls. Listing’s plane of the eye with greater ophthalmoplegia was increased in thickness. After IVIG treatment, the range of eye movements improved, but saccades remained faster than those of controls. Also, no fatigue was observed and the thickness of Listing’s plane was reduced towards the normal range. Increased peak velocity, despite progressive hypometria due to fatigue, supports the hypothesis that the pale global extraocular muscle fibers are relatively spared in myasthenia. Involvement of other extraocular muscle fiber types leads to limited range of eye movements and an increase in the thickness of Listing’s plane.
PMCID: PMC3166887  PMID: 19645950
saccades; fatigue; pale extraocular muscle fibers; Listing’s plane
7.  Selective Defects of Visual Tracking in Progressive Supranuclear Palsy (PSP): Implications for mechanisms of motion vision 
Vision research  2010;50(8):761-771.
Smooth ocular tracking of a moving visual stimulus comprises a range of responses that encompass the ocular following response (OFR), a pre-attentive, short-latency mechanism, and smooth pursuit, which directs the retinal fovea at the moving stimulus. In order to determine how interdependent these two forms of ocular tracking are, we studied vertical OFR in progressive supranuclear palsy (PSP), a parkinsonian disorder in which vertical smooth pursuit is known to be impaired. We measured eye movements of 9 patients with PSP and 12 healthy control subjects. Subjects viewed vertically moving sine-wave gratings that had a temporal frequency of 16.7 Hz, contrast of 32%, and spatial frequencies of 0.17, 0.27 or 0.44 cycles/°. We measured OFR amplitude as change in eye position in the 70 – 150 ms, open-loop interval following stimulus onset. Vertical smooth pursuit was studied as subjects attempted to track a 0.27 cycles/° grating moving sinusoidally through several cycles at frequencies between 0.1 – 2.5 Hz. We found that OFR amplitude, and its dependence on spatial frequency, was similar in PSP patients (group mean 0.10°) and control subjects (0.11°), but the latency to onset of OFR was greater for PSP patients (group mean 99 ms) than control subjects (90 ms). When OFR amplitude was re-measured, taking into account the increased latency in PSP patients, there was still no difference from control subjects. We confirmed that smooth pursuit was consistently impaired in PSP; group mean tracking gain at 0.7 Hz was 0.29 for PSP patients and 0.63 for controls. Neither PSP patients nor control subjects showed any correlation between OFR amplitude and smooth-pursuit gain. We propose that OFR is spared because it is generated by low-level motion processing that is dependent on posterior cerebral cortex, which is less affected in PSP. Conversely, smooth pursuit depends more on projections from frontal cortex to the pontine nuclei, both of which are involved in PSP. The accessory optic pathway, which is heavily involved in PSP, seems unlikely to contribute to the OFR in humans.
PMCID: PMC2846391  PMID: 20123108
Smooth pursuit; ocular following response; pontine nuclei; tau protein
8.  Cross-Over Trial of Gabapentin and Memantine as Treatment for Acquired Nystagmus 
Annals of neurology  2010;67(5):676-680.
We conducted a masked, cross-over, therapeutic trial of gabapentin (1200mg/day) versus memantine (40mg/day) for acquired nystagmus in 10 patients (28–61 years; 7 female; MS: 3, post-stroke: 6, post-traumatic: 1). Nystagmus was pendular in 6 patients (oculopalatal tremor: 4, MS: 2) and jerk upbeat, hemi-seesaw, torsional, or upbeat-diagonal in each of the others. Both drugs reduced median eye speed (p<0.001), gabapentin by 32.8% and memantine by 27.8%, and improved visual acuity (p<0.05). Each patient improved with one or both drugs. Side-effects included unsteadiness with gabapentin and lethargy with memantine. Both drugs should be considered as treatment for acquired forms of nystagmus.
PMCID: PMC3064518  PMID: 20437565
nystagmus; oscillopsia; multiple sclerosis; oculopalatal tremor
9.  The Disturbance of Gaze in Progressive Supranuclear Palsy: Implications for Pathogenesis 
Progressive supranuclear palsy (PSP) is a disease of later life that is currently regarded as a form of neurodegenerative tauopathy. Disturbance of gaze is a cardinal clinical feature of PSP that often helps clinicians to establish the diagnosis. Since the neurobiology of gaze control is now well understood, it is possible to use eye movements as investigational tools to understand aspects of the pathogenesis of PSP. In this review, we summarize each disorder of gaze control that occurs in PSP, drawing on our studies of 50 patients, and on reports from other laboratories that have measured the disturbances of eye movements. When these gaze disorders are approached by considering each functional class of eye movements and its neurobiological basis, a distinct pattern of eye movement deficits emerges that provides insight into the pathogenesis of PSP. Although some aspects of all forms of eye movements are affected in PSP, the predominant defects concern vertical saccades (slow and hypometric, both up and down), impaired vergence, and inability to modulate the linear vestibulo-ocular reflex appropriately for viewing distance. These vertical and vergence eye movements habitually work in concert to enable visuomotor skills that are important during locomotion with the hands free. Taken with the prominent early feature of falls, these findings suggest that PSP tauopathy impairs a recently evolved neural system concerned with bipedal locomotion in an erect posture and frequent gaze shifts between the distant environment and proximate hands. This approach provides a conceptual framework that can be used to address the nosological challenge posed by overlapping clinical and neuropathological features of neurodegenerative tauopathies.
PMCID: PMC3008928  PMID: 21188269
saccades; vergence; vestibular; parkinsonian disorders; tauopathy
10.  Neuromuscular transmission failure in myasthenia gravis: decrement of safety factor and susceptibility of extraocular muscles 
An appropriate density of acetylcholine receptors (AChRs) and Na+ channels (NaChs) in the normal neuromuscular junction (NMJ) determines the magnitude of safety factor (SF) that guarantees fidelity of neuromuscular transmission. In myasthenia gravis (MG), an overall simplification of the postsynaptic folding secondary to NMJ destruction results in AChRs and NaChs depletion. Loss of AChRs and NaChs accounts respectively for 59% and 40% reduction of the SF at the endplate, which manifests as neuromuscular transmission failure. The extraocular muscles (EOM) have physiologically less developed postsynaptic folding, hence a lower baseline SF, which predisposes them to dysfunction in MG and development of fatigue during “high performance” eye movements, such as saccades. However, saccades in MG show stereotyped, conjugate initial components, similar to normal, which might reflect preserved neuromuscular transmission fidelity at the NMJ of the fast, pale global fibers, which have better developed postsynaptic folding than other extraocular fibers.
PMCID: PMC3539765  PMID: 23278588
safety factor; extraocular muscles; saccades; neuromuscular junction
11.  Miller Fisher Syndrome Mimicking Ocular Myasthenia Gravis 
Miller Fisher syndrome (MFS) is a rare immune-mediated neuropathy that commonly presents with diplopia following the acute onset of complete bilateral external ophthalmoplegia. Ophthalmoplegia is often accompanied by other neurological deficits such as ataxia and areflexia that characterize MFS. Although MFS is a clinical diagnosis, serological confirmation is possible by identifying the anti-GQ1b antibody found in a majority of affected patients. We report a patient with MFS who presented with clinical signs suggestive of ocular myasthenia gravis, but in whom the correct diagnosis was made on the basis of serological testing for the anti-GQ1b antibody.
Case Report
An 81-year-old white man presented with an acute onset of diplopia following a mild gastrointestinal illness. Clinical examination revealed complete bilateral external ophthalmoplegia and left-sided ptosis. He developed more marked bilateral ptosis, left greater than right, with prolonged attempted upgaze. He was also noted to have a Cogan’s lid twitch. Same day evaluation by a neuro-ophthalmologist revealed mild left-sided facial and bilateral orbicularis oculi weakness. He had no limb ataxia, but exhibited a slightly wide-based gait with difficulty walking heel-to-toe. A provisional diagnosis of ocular myasthenia gravis was made and anticholinesterase inhibitor therapy was initiated. However, his symptoms did not improve and serological testing was positive for the anti-GQ1b IgG antibody, supporting a diagnosis of MFS.
Although the predominant ophthalmic feature of MFS is complete bilateral external ophthalmoplegia, it should be recognized that MFS has variable associations with lid and pupillary dysfunction. Such confounding neuro-ophthalmic features require a thorough history, neurological examination, neuroimaging, and serological testing for the anti-GQ1b antibody to arrive at a diagnosis of MFS.
PMCID: PMC3516407  PMID: 23190719
Miller Fisher syndrome; anti-ganglioside antibody; ophthalmoplegia; diplopia; cranial neuropathies; multiple; myasthenia gravis; ocular
12.  The Human Vertical Translation Vestibulo-ocular Reflex (tVOR): Normal and Abnormal Responses 
Geometric considerations indicate that the human translational vestibulo-ocular reflex (tVOR) should have substantially different properties than the angular vestibulo-ocular reflex (aVOR). Specifically, tVOR cannot simultaneously stabilize images of distant and near objects on the retina. Most studies make the tacit assumption that tVOR acts to stabilize foveal images even though, in humans, tVOR is reported to compensate for less than 60% of foveal image motion. We have determined that the compensation gain (eye rotational velocity / required eye rotational velocity to maintain foveal target fixation) of tVOR is held steady at ~ 0.6 during viewing of either near or distant targets during vertical (bob) translations in ambient illumination. We postulate that tVOR evolved not to stabilize the image of the target on the fovea, but rather to minimize retinal image motion between objects lying in different depth planes, in order to optimize motion parallax information. Such behavior is optimized when binocular visual cues of both far and distant targets are available in ambient light. Patients with progressive supranuclear palsy or cerebellar ataxia show impaired ability to increase tVOR responses appropriately when they view near targets. In cerebellar patients, impaired ability to adjust tVOR responses to viewing conditions occurs despite intact ability to converge at near. Loss of the ability to adjust tVOR according to viewing conditions appears to represent a distinct disorder of vestibular function.
PMCID: PMC2858323  PMID: 19645882
Locomotion; moving platform; motional parallax; PSP; cerebellar ataxia
13.  Diagnosing disconjugate eye movements 
Neurology  2008;71(15):1167-1175.
Saccades are fast eye movements that conjugately shift the point of fixation between distant features of interest in the visual environment. Several disorders, affecting sites from brainstem to extraocular muscle, may cause horizontal saccades to become disconjugate. Prior techniques for detection of saccadic disconjugacy, especially in internuclear ophthalmoparesis (INO), have compared only one point in abducting vs adducting saccades, such as peak velocity.
We applied a phase-plane technique that compared each eye’s velocity as a function of change in position (normalized displacement) in 22 patients with disease variously affecting the brainstem reticular formation, the abducens nucleus, the medial longitudinal fasciculus, the oculomotor nerve, the abducens nerve, the neuromuscular junction, or the extraocular muscles; 10 age-matched subjects served as controls.
We found three different patterns of disconjugacy throughout the course of horizontal saccades: early abnormal velocity disconjugacy during the first 10% of the displacement in patients with INO, oculomotor or abducens nerve palsy, and advanced extraocular muscle disease; late disconjugacy in patients with disease affecting the neuromuscular junction; and variable middle-course disconjugacy in patients with pontine lesions. When normal subjects made disconjugate saccades between two targets aligned on one eye, the initial part of the movement remained conjugate.
Along with conventional measures of saccades, such as peak velocity, phase planes provide a useful tool to determine the site, extent, and pathogenesis of disconjugacy. We hypothesize that the pale global extraocular muscle fibers, which drive the high-acceleration component of saccades, receive a neural command that ensures initial ocular conjugacy.
= abducens;
= cranial nerve;
= chronic progressive external ophthalmoplegia;
= eye movement;
= horizontal;
= internuclear ophthalmoparesis;
= myasthenia gravis;
= medial longitudinal fasciculus;
= multiple sclerosis;
= patient;
= prediction interval;
= paramedian pontine reticular formation;
= raphe interpositus;
= vertical.
PMCID: PMC2586990  PMID: 18838664
14.  Ocular-Motor Profile and Effects of Memantine in a Familial Form of Adult Cerebellar Ataxia with Slow Saccades and Square Wave Saccadic Intrusions 
PLoS ONE  2013;8(7):e69522.
Fixation instability due to saccadic intrusions is a feature of autosomal recessive spinocerebellar ataxias, and includes square wave intrusions (SWI) and macrosaccadic oscillations (MSO). A recent report suggested that the non-competitive antagonist of NMDA receptors, memantine, could decrease MSO and improve fixation in patients with spinocerebellar ataxia with saccadic intrusions (SCASI). We similarly tested two sisters, respectively of 58 and 60 years, with an unrecognized form of recessive, adult-onset cerebellar ataxia, peripheral neuropathy and slow saccades, who showed prominent SWI and also complained with difficulty in reading. We tested horizontal visually guided saccades (10°–18°) and three minutes of steady fixation in each patient and in thirty healthy controls. Both patients showed a significant reduction of peak and mean velocity compared with control subjects. Large SWI interrupting steady fixation were prominent during steady fixation and especially following visually guided saccades. Eye movements were recorded before and during the treatment with memantine, 20 mg/daily for 6 months. The treatment with memantine reduced both the magnitude and frequency of SWI (the former significantly), but did not modified neurological conditions or saccade parameters. Thus, our report suggests that memantine may have some general suppressive effect on saccadic intrusions, including both SWI and MSO, thereby restoring the capacity of reading and visual attention in these and in other recessive forms of ataxia, including Friedreich’s, in which saccadic intrusions are prominent.
PMCID: PMC3718679  PMID: 23894498
15.  Diagnosing Disconjugate Eye Movements 
Neurology  2008;71(15):1167-1175.
Saccades are fast eye movements that conjugately shift the point of fixation between distant features of interest in the visual environment. Several disorders, affecting sites from brainstem to extraocular muscle, may cause horizontal saccades to become disconjugate. Prior techniques for detection of saccadic disconjugacy, especially in internuclear ophthalmoparesis (INO), have compared only one point in abducting versus adducting saccades, such as peak velocity.
We applied a phase-plane technique that compared each eye’s velocity as a function of change in position (normalized displacement) in 22 patients with disease variously affecting the brainstem reticular formation, the abducens nucleus, the medial longitudinal fasciculus, the oculomotor nerve, the abducens nerve, the neuromuscular junction or the extraocular muscles; 10 age-matched subjects served as controls.
We found three different patterns of disconjugacy throughout the course of horizontal saccades: early abnormal velocity disconjugacy during the first 10% of the displacement, in patients with INO, oculomotor or abducens nerve palsy and advanced extraocular muscle disease; late disconjugacy in patients with disease affecting the neuromuscular junction; and variable middle-course disconjugacy in patients with pontine lesions. When normal subjects made disconjugate saccades between two targets aligned on one eye, the initial part of the movement remained conjugate.
Along with conventional measures of saccades, such as peak velocity, phase-planes provide a useful tool to determine the site, extent, and pathogenesis of disconjugacy. We hypothesize that the pale global extraocular muscle fibers, which drive the high-acceleration component of saccades, receive a neural command that ensures initial ocular conjugacy.
PMCID: PMC2586990  PMID: 18838664
Pontine infarction; multiple sclerosis; internuclear ophthalmoplegia; abducens nerve palsy; oculomotor nerve palsy; myasthenia gravis; chronic progressive external ophthalmoplegia
16.  Contrast Sensitivity, First-Order Motion and Initial Ocular Following in Demyelinating Optic Neuropathy 
Journal of neurology  2006;253(9):1203-1209.
The ocular following response (OFR) is a measure of motion vision elicited at ultra-short latencies by sudden movement of a large visual stimulus. We compared the OFR to vertical sinusoidal gratings (spatial frequency 0.153 cycles/° or 0.458 cycles/°) of each eye in a subject with evidence of left optic nerve demyelination due to multiple sclerosis (MS). The subject showed substantial differences in vision measured with stationary low-contrast Sloan letters (20/63 OD and 20/200 OS at 2.5% contrast) and the Lanthony Desaturated 15-hue color test (Color Confusion Index 1.11 OD and 2.14 OS). Compared with controls, all of the subject's OFR to increasing contrast showed a higher threshold. The OFR of each of the subject's eyes were similar for the 0.153 cycles/° stimulus, and psychophysical measurements of his ability to detect these moving gratings were also similar for each eye. However, with the 0.458 cycles/° stimulus, the subject's OFR was asymmetric and the affected eye showed decreased responses (smaller slope constant as estimated by the Naka-Rushton equation). These results suggest that, in this case, optic neuritis caused a selective deficit that affected parvocellular pathways mediating higher spatial frequencies, lower-contrast, and color vision, but spared the field-holding mechanism underlying the OFR to lower spatial frequencies. The OFR may provide a useful method to study motion vision in individuals with disorders affecting anterior visual pathways.
PMCID: PMC2408647  PMID: 16649097
optic neuritis; multiple sclerosis; saccades; pursuit
17.  Saccades during Attempted Fixation in Parkinsonian Disorders and Recessive Ataxia: From Microsaccades to Square-Wave Jerks 
PLoS ONE  2013;8(3):e58535.
During attempted visual fixation, saccades of a range of sizes occur. These “fixational saccades” include microsaccades, which are not apparent in regular clinical tests, and “saccadic intrusions”, predominantly horizontal saccades that interrupt accurate fixation. Square-wave jerks (SWJs), the most common type of saccadic intrusion, consist of an initial saccade away from the target followed, after a short delay, by a “return saccade” that brings the eye back onto target. SWJs are present in most human subjects, but are prominent by their increased frequency and size in certain parkinsonian disorders and in recessive, hereditary spinocerebellar ataxias. Here we asked whether fixational saccades showed distinctive features in various parkinsonian disorders and in recessive ataxia. Although some saccadic properties differed between patient groups, in all conditions larger saccades were more likely to form SWJs, and the intervals between the first and second saccade of SWJs were similar. These findings support the proposal of a common oculomotor mechanism that generates all fixational saccades, including microsaccades and SWJs. The same mechanism also explains how the return saccade in SWJs is triggered by the position error that occurs when the first saccadic component is large, both in the healthy brain and in neurological disease.
PMCID: PMC3596296  PMID: 23516502
18.  Neurological Basis for Eye Movements of the Blind 
PLoS ONE  2013;8(2):e56556.
When normal subjects fix their eyes upon a stationary target, their gaze is not perfectly still, due to small movements that prevent visual fading. Visual loss is known to cause greater instability of gaze, but reported comparisons with normal subjects using reliable measurement techniques are few. We measured binocular gaze using the magnetic search coil technique during attempted fixation (monocular or binocular viewing) of 4 individuals with childhood-onset of monocular visual loss, 2 individuals with late-onset monocular visual loss due to age-related macular degeneration, 2 individuals with bilateral visual loss, and 20 healthy control subjects. We also measured saccades to visual or somatosensory cues. We tested the hypothesis that gaze instability following visual impairment is caused by loss of inputs that normally optimize the performance of the neural network (integrator), which ensures both monocular and conjugate gaze stability. During binocular viewing, patients with early-onset monocular loss of vision showed greater instability of vertical gaze in the eye with visual loss and, to a lesser extent, in the normal eye, compared with control subjects. These vertical eye drifts were much more disjunctive than upward saccades. In individuals with late monocular visual loss, gaze stability was more similar to control subjects. Bilateral visual loss caused eye drifts that were larger than following monocular visual loss or in control subjects. Accurate saccades could be made to somatosensory cues by an individual with acquired blindness, but voluntary saccades were absent in an individual with congenital blindness. We conclude that the neural gaze-stabilizing network, which contains neurons with both binocular and monocular discharge preferences, is under adaptive visual control. Whereas monocular visual loss causes disjunctive gaze instability, binocular blindness causes both disjunctive and conjugate gaze instability (drifts and nystagmus). Inputs that bypass this neural network, such as projections to motoneurons for upward saccades, remain conjugate.
PMCID: PMC3575504  PMID: 23441203
19.  Do brainstem omnipause neurons terminate saccades? 
Saccade-generating burst neurons (BN) are inhibited by omnipause neurons (OPN), except during saccades. OPN activity pauses before saccade onset and resumes at the saccade end. Microstimulation of OPN stops saccades in mid-flight, which shows that OPN can end saccades. However, OPN pause duration does not correlate well with saccade duration, and saccades are normometric after OPN lesions. We tested whether OPN were responsible for stopping saccades both in late-onset Tay–Sachs, which causes premature saccadic termination, and in individuals with cerebellar hypermetria. We studied gaze shifts between two targets at different distances aligned on one eye, which consist of a disjunctive saccade followed by vergence. High-frequency conjugate oscillations during the vergence movements that followed saccades were present in all subjects studied, indicating OPN silence. Thus, mechanisms other than OPN discharge (e.g., cerebellar caudal fastigial nucleus–promoting inhibitory BN discharge) must contribute to saccade termination.
PMCID: PMC3438674  PMID: 21950975
Tay–Sachs disease; saccades; omnipause neurons; fastigial nucleus; Müller paradigm
20.  Treatable Neurological Disorders Misdiagnosed as Creutzfeldt - Jakob disease 
Annals of neurology  2011;70(3):437-444.
Heightened awareness of Creutzfeldt-Jakob disease (CJD) among physicians and the lay public has led to its frequent consideration in the differential diagnosis of patients with rapidly progressive dementia (RPD). Our goal was to determine which treatable disorders are most commonly mistaken for CJD.
We performed a retrospective clinical and neuropathological review of prion-negative brain autopsy cases referred to the US National Prion Disease Pathology Surveillance Center (NPDPSC) at Case Western Reserve University from January 2006 through December 2009.
Of 1,106 brain autopsies, 352 (32%) were negative for prion disease, 304 of which had adequate tissue for histopathological analysis. Alzheimer disease (154) and vascular dementia (36) were the two most frequent diagnoses. Seventy one patients had potentially treatable diseases. Clinical findings included dementia (42 cases), pyramidal (20), cerebellar (14), or extrapyramidal (12) signs, myoclonus (12), visual disturbance (9) and akinetic mutism (5); a typical electroencephalogram occurred only once. Neuropathological diagnoses included immune-mediated disorders (26), neoplasia (25, most often lymphoma), infections (14), and metabolic disorders (6).
In patients with RPD, treatable disorders should be considered and excluded before diagnosing CJD. Misdiagnosed patients often did not fulfill WHO criteria. RPD with positive 14-3-3 CSF protein should not be regarded as sufficient for the diagnosis of CJD. Adherence to revised criteria for CJD, which include distinctive MRI features of prion disease, is likely to improve diagnostic accuracy.
PMCID: PMC3170496  PMID: 21674591
21.  Paraneoplastic disorders of eye movements 
Paraneoplastic syndromes affecting the brainstem and cerebellum are reported to cause a variety of abnormalities of eye movements. Recent studies have begun to account for the mechanisms underlying several syndromes, characterized by opsoclonus, slow, or dysmetric saccades, as well as downbeat nystagmus. We provide evidence that upbeat nystagmus in a patient with pancreatic cancer reflected a cerebellar-induced imbalance of otolithic pathways: she showed marked retropulsion, and her nystagmus was dependent on head position, being absent when supine, and suppressed with convergence. In addition to anti-Hu antibodies, we demonstrated antibodies to a novel neuronal cell surface antigen. Taken with other recent studies, our findings suggest that paraneoplastic syndromes arise due to antibodies against surface neuronal antigens, including receptors and channels. Abnormal eye movements in paraneoplastic syndromes offer insights into the pathogenesis of these disorders and the opportunity to test potential therapies, such as new drugs with effects on neuronal channels.
PMCID: PMC3187877  PMID: 21951005
upbeat nystagmus; oscillopsia; pancreatic endocrine; neoplasm
22.  Pharmacological tests of hypotheses for acquired pendular nystagmus 
Acquired pendular nystagmus (APN) occurs with multiple sclerosis (MS) and oculopalatal tremor (OPT); distinct features of the nystagmus have led to the development of separate models for the pathogenesis. APN in MS has been attributed to instability in the neural integrator, which normally ensures steady gaze. APN in OPT may result from electrotonic coupling between neurons in the hypertrophied inferior olivary nucleus, which induces maladaptive learning in cerebellar cortex. We tested these two hypotheses by analyzing the effects of gabapentin, memantine, and baclofen on both forms of nystagmus. No drug changed the dominant frequency of either form of APN, but the variability of frequency was affected with gabapentin and memantine in patients with OPT. The amplitude of APN in both MS and OPT was reduced with gabapentin and memantine, but not baclofen. Analyzing the effects of drug therapies on ocular oscillations provides a novel approach to test models of nystagmus.
PMCID: PMC3187918  PMID: 21951011
cerebellum; inferior olive; plasticity; learning; Guillain–Mollaret triangle; multiple sclerosis
23.  The effects of ion channel blockers validate the conductance-based model of saccadic oscillations 
Conductance-based models of reciprocally inhibiting burst neurons suggest that intrinsic membrane properties and postinhibitory rebound (PIR) determine the amplitude and frequency of saccadic oscillations. Reduction of the low-threshold calcium currents (IT) in the model decreased the amplitude but increased the frequency of the simulated oscillations. Combined reduction of hyperpolarization-activated cation current (Ih) and IT in the model abolished the simulated oscillations. We measured the effects of a selective blocker of IT (ethosuximide) in healthy subjects on the amplitude and frequency of saccadic oscillations evoked by eye closure and of a nonselective blocker of Ih and IT (propronolol) in a patient with microsaccadic oscillation and limb tremor syndrome (mSOLT). Ethosuximide significantly reduced the amplitude but increased the frequency of the saccadic oscillations during eye closure in healthy subjects. Propranolol abolished saccadic oscillations in the mSOLT patient. These results support the hypothetical role of postinhibitory rebound, Ih, and IT, in generation of saccadic oscillations and determining their kinematic properties.
PMCID: PMC3431800  PMID: 21950976
burst neurons; hyperpolarization-activated cation current; low-threshold calcium current; reciprocal innervations
25.  The role of the medial longitudinal fasciculus in horizontal gaze: tests of current hypotheses for saccade-vergence interactions 
Rapid shifts of the point of visual fixation between equidistant targets require equal-sized saccades of each eye. The brainstem medial longitudinal fasciculus (MLF) plays a cardinal role in ensuring that horizontal saccades between equidistant targets are tightly yoked. Lesions of the MLF—internuclear ophthalmoparesis (INO)—cause horizontal saccades to become disjunctive: adducting saccades are slow, small, or absent. However, in INO, convergence movements may remain intact. We studied horizontal gaze shifts between equidistant targets and between far and near targets aligned on the visual axis of one eye (Müller test paradigm) in five cases of INO and five control subjects. We estimated the saccadic component of each movement by measuring peak velocity and peak acceleration. We tested whether the ratio of the saccadic component of the adducting/abducting eyes stayed constant or changed for the two types of saccades. For saccades made by control subjects between equidistant targets, the group mean ratio (±SD) of adducting/abducting peak velocity was 0.96 ± 0.07 and adducting/abducting peak acceleration was 0.94 ± 0.09. Corresponding ratios for INO cases were 0.45 ± 0.10 for peak velocity and 0.27 ± 0.11 for peak acceleration, reflecting reduced saccadic pulses for adduction. For control subjects, during the Müller paradigm, the adducting/abducting ratio was 1.25 ± 0.14 for peak velocity and 1.03 ± 0.12 for peak acceleration. Corresponding ratios for INO cases were 0.82 ± 0.18 for peak velocity and 0.48 ± 0.13 for peak acceleration. When adducting/abducting ratios during Müller versus equidistant targets paradigms were compared, INO cases showed larger relative increases for both peak velocity and peak acceleration compared with control subjects. Comparison of similar-sized movements during the two test paradigms indicated that whereas INO patients could decrease peak velocity of their abducting eye during the Müller paradigm, they were unable to modulate adducting velocity in response to viewing conditions. However, the initial component of each eye’s movement was similar in both cases, possibly reflecting activation of saccadic burst neurons. These findings support the hypothesis that horizontal saccades are governed by disjunctive signals, preceded by an initial, high-acceleration conjugate transient and followed by a slower vergence component.
PMCID: PMC3039121  PMID: 21082311
Eye movements; Saccades; Vergence; Medial longitudinal fasciculus; Hering’s law; Multiple sclerosis; Internuclear ophthalmoplegia

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