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1.  Automatic segmentation of microcystic macular edema in OCT 
Biomedical Optics Express  2014;6(1):155-169.
Microcystic macular edema (MME) manifests as small, hyporeflective cystic areas within the retina. For reasons that are still largely unknown, a small proportion of patients with multiple sclerosis (MS) develop MME—predominantly in the inner nuclear layer. These cystoid spaces, denoted pseudocysts, can be imaged using optical coherence tomography (OCT) where they appear as small, discrete, low intensity areas with high contrast to the surrounding tissue. The ability to automatically segment these pseudocysts would enable a more detailed study of MME than has been previously possible. Although larger pseudocysts often appear quite clearly in the OCT images, the multi-frame averaging performed by the Spectralis scanner adds a significant amount of variability to the appearance of smaller pseudocysts. Thus, simple segmentation methods only incorporating intensity information do not perform well. In this work, we propose to use a random forest classifier to classify the MME pixels. An assortment of both intensity and spatial features are used to aid the classification. Using a cross-validation evaluation strategy with manual delineation as ground truth, our method is able to correctly identify 79% of pseudocysts with a precision of 85%. Finally, we constructed a classifier from the output of our algorithm to distinguish clinically identified MME from non-MME subjects yielding an accuracy of 92%.
doi:10.1364/BOE.6.000155
PMCID: PMC4317118  PMID: 25657884
(100.0100) Image processing; (170.4470) Ophthalmology; (170.4500) Optical coherence tomography
2.  Long-term Outcomes in Ranibizumab-Treated Patients With Retinal Vein Occlusion; The Role of Progression of Retinal Nonperfusion 
American journal of ophthalmology  2013;156(4):693-705.
PURPOSE
To determine the percentage of ranibizumab-treated patients with retinal vein occlusion (RVO) who had resolution of edema for at least 6 months after the last injection, along with factors and outcomes that correlate with resolution.
DESIGN
Post hoc analysis of open-label clinical trial.
METHODS
Twenty patients with branch RVO (BRVO) and 20 with central RVO (CRVO) received ranibizumab monthly for 3 months and as needed for recurrent/persistent macular edema, no more frequently than every 2 months. Patients still requiring injections after month 40 received scatter and grid laser photocoagulation to try to reduce the need for injections. Main outcome measures included the percentage of patients who had resolution of edema, change in best-corrected visual acuity (BCVA) from baseline, and change in area of retinal nonperfusion in central subfields.
RESULTS
Nine patients with BRVO (45%) had edema resolution from injections alone after a mean of 20.2 months, 4 resolved after addition of laser, 4 were unresolved through 72 months, and 3 exited prior to resolution. Five patients with CRVO (25%) resolved from injections alone after a mean of 14.0 months, 8 remained unresolved through 72 months despite addition of laser, and 7 exited prior to resolution. For BRVO or CRVO, there was a negative correlation between posterior retinal nonperfusion area and BCVA at months 18, 24, and 36 (P < .05).
CONCLUSIONS
In patients with RVO, infrequent ranibizumab injections to control edema may not be sufficient to prevent progression of retinal nonperfusion, which may contribute to loss of visual gains.
doi:10.1016/j.ajo.2013.05.039
PMCID: PMC4030598  PMID: 24053892
3.  Comparison of Time- and Spectral-Domain Optical Coherence Tomography in Management of Diabetic Macular Edema 
Purpose.
Some clinical trials that proved the benefits of anti-VEGF therapy for diabetic macular edema (DME) based retreatment decisions on visual acuity and time-domain ocular coherence tomography (TD-OCT) central subfield thickness changes since the last treatment. This study assessed the impact of TD-OCT followed by spectral domain (SD)-OCT on as needed treatment decision-making in the management of DME with anti-VEGF medications.
Methods.
Patients previously treated for DME with anti-VEGF medications in the Retina Division of the Wilmer Eye Institute, following an institutional review board–approved informed consent process, underwent clinical examination, TD-, and SD-OCT imaging. Their retina specialists recorded whether additional anti-VEGF therapy was recommended and their level of certainty in the decision after performing a clinical examination and reviewing a TD-OCT, and then again after reviewing a SD-OCT.
Results.
Data were collected for 129 treatment decision pairs involving 67 eyes from 46 subjects. Nonconcordant decisions occurred in 9 (7%) treatment decision pairs. In 7 of these (5%, 95% confidence interval [CI]: 2%–11%), the addition of SD-OCT changed the retina specialist's decision from not recommending to recommending retreatment. The addition of SD-OCT increased the certainty of the retina specialist in 36% (95% CI: 27%–45%) of all treatment decision pairs.
Conclusions.
Spectral-domain OCT does not appear to change the ultimate treatment decision or increase the level of certainty of the retina specialist relative to TD-OCT in most cases of DME under anti-VEGF management in clinical practice. The few nonconcordant decisions appear to trend toward recommending more anti-VEGF therapy following SD-OCT.
Spectral-domain optical coherence tomography (SD-OCT) does not appear to change the ultimate treatment decision or increase the level of certainty of the retina specialist relative to time-domain OCT in most cases of diabetic macular edema under anti-VEGF management in clinical practice.
doi:10.1167/iovs.13-13049
PMCID: PMC3945899  PMID: 24526445
optical coherence tomography; macular edema; diabetic retinopathy
4.  Revisiting corrective saccades: role of visual feedback 
Vision research  2013;89:54-64.
To clarify the role of visual feedback in the generation of corrective movements after inaccurate primary saccades, we used a visually-triggered saccade task in which we varied how long the target was visible. The target was on for only 100 ms (OFF100ms), on until the start of the primary saccade (OFFonset) or on for 2 s (ON). We found that the tolerance for the post-saccadic error was small (− 2%) with a visual signal (ON) but greater (−6%) without visual feedback (OFF100ms). Saccades with an error of −10%, however, were likely to be followed by corrective saccades regardless of whether or not visual feedback was present. Corrective saccades were generally generated earlier when visual error information was available; their latency was related to the size of the error. The LATER (Linear Approach to Threshold with Ergodic Rate) model analysis also showed a comparable small population of short latency corrective saccades irrespective of the target visibility. Finally, we found, in the absence of visual feedback, the accuracy of corrective saccades across subjects was related to the latency of the primary saccade. Our findings provide new insights into the mechanisms underlying the programming of corrective saccades: 1) the preparation of corrective saccades begins along with the preparation of the primary saccades, 2) the accuracy of corrective saccades depends on the reaction time of the primary saccades and 3) if visual feedback is available after the initiation of the primary saccade, the prepared correction can be updated.
doi:10.1016/j.visres.2013.07.012
PMCID: PMC3784029  PMID: 23891705
Primary saccade; Corrective saccade; Visual feedback; LATER model; Forward control
5.  Analysis of macular OCT images using deformable registration 
Biomedical Optics Express  2014;5(7):2196-2214.
Optical coherence tomography (OCT) of the macula has become increasingly important in the investigation of retinal pathology. However, deformable image registration, which is used for aligning subjects for pairwise comparisons, population averaging, and atlas label transfer, has not been well–developed and demonstrated on OCT images. In this paper, we present a deformable image registration approach designed specifically for macular OCT images. The approach begins with an initial translation to align the fovea of each subject, followed by a linear rescaling to align the top and bottom retinal boundaries. Finally, the layers within the retina are aligned by a deformable registration using one-dimensional radial basis functions. The algorithm was validated using manual delineations of retinal layers in OCT images from a cohort consisting of healthy controls and patients diagnosed with multiple sclerosis (MS). We show that the algorithm overcomes the shortcomings of existing generic registration methods, which cannot be readily applied to OCT images. A successful deformable image registration algorithm for macular OCT opens up a variety of population based analysis techniques that are regularly used in other imaging modalities, such as spatial normalization, statistical atlas creation, and voxel based morphometry. Examples of these applications are provided to demonstrate the potential benefits such techniques can have on our understanding of retinal disease. In particular, included is a pilot study of localized volumetric changes between healthy controls and MS patients using the proposed registration algorithm.
doi:10.1364/BOE.5.002196
PMCID: PMC4102359  PMID: 25071959
(100.0100) Image processing; (170.4470) Ophthalmology; (170.4500) Optical coherence tomography
6.  Development and Validation of a Falls Grading Scale 
Journal of geriatric physical therapy (2001)  2013;36(2):10.1519/JPT.0b013e31825f6777.
Background and Purpose
The recording of fall events is usually subjective and imprecise, which limits clinical practice and falls-related research. We sought to develop and validate a scale to grade near-fall and fall events based on their severity represented by the use of healthcare resources, with the goal of standardizing fall reporting in the clinical and research settings.
Methods
Qualitative instrument development was based on a literature review and semi-structured interviews to assess face and content validity. We queried older individuals and healthcare professionals with expertise in the care of patients at risk of falling about clinically important differences to detect and how to optimize the scale's ease of use. To assess the scale's inter-rater reliability, we created 30 video-vignettes of falls and compared how healthcare professionals and volunteers rated each of the falls according to our grading scale.
Results
We developed the illustrated 4-point Hopkins Falls Grading Scale (HFGS). The grades distinguish a near-fall (Grade 1) from a fall for which an individual did not receive medical attention (Grade 2), a fall associated with medical attention but not hospital admission (Grade 3), and a fall associated with hospital admission (Grade 4). Overall, the HFGS exhibited good face and content validity, and had an intraclass correlation coefficient of 0.998.
Conclusion
The 4-point HFGS demonstrates good face and content validity and high inter-rater reliability. We predict this tool will facilitate the standardization of falls reporting in both the clinical and research settings.
doi:10.1519/JPT.0b013e31825f6777
PMCID: PMC3867809  PMID: 22810170
Falls definition; falls classification; falls reporting
7.  Multiple-object geometric deformable model for segmentation of macular OCT 
Biomedical Optics Express  2014;5(4):1062-1074.
Optical coherence tomography (OCT) is the de facto standard imaging modality for ophthalmological assessment of retinal eye disease, and is of increasing importance in the study of neurological disorders. Quantification of the thicknesses of various retinal layers within the macular cube provides unique diagnostic insights for many diseases, but the capability for automatic segmentation and quantification remains quite limited. While manual segmentation has been used for many scientific studies, it is extremely time consuming and is subject to intra- and inter-rater variation. This paper presents a new computational domain, referred to as flat space, and a segmentation method for specific retinal layers in the macular cube using a recently developed deformable model approach for multiple objects. The framework maintains object relationships and topology while preventing overlaps and gaps. The algorithm segments eight retinal layers over the whole macular cube, where each boundary is defined with subvoxel precision. Evaluation of the method on single-eye OCT scans from 37 subjects, each with manual ground truth, shows improvement over a state-of-the-art method.
doi:10.1364/BOE.5.001062
PMCID: PMC3986003  PMID: 24761289
(100.0100) Image processing; (170.4470) Ophthalmology; (170.4500) Optical coherence tomography
8.  Principal Component Analysis of Cerebellar Shape on MRI Separates SCA Types 2 and 6 into Two Archetypal Modes of Degeneration 
Cerebellum (London, England)  2012;11(4):887-895.
Although “cerebellar ataxia” is often used in reference to a disease process, presumably there are different underlying pathogenetic mechanisms for different subtypes. Indeed, spinocerebellar ataxia (SCA) types 2 and 6 demonstrate complementary phenotypes, thus predicting a different anatomic pattern of degeneration. Here, we show that an unsupervised classification method, based on principal component analysis (PCA) of cerebellar shape characteristics, can be used to separate SCA2 and SCA6 into two classes, which may represent disease-specific archetypes. Patients with SCA2 (n=11) and SCA6 (n=7) were compared against controls (n=15) using PCA to classify cerebellar anatomic shape characteristics. Within the first three principal components, SCA2 and SCA6 differed from controls and from each other. In a secondary analysis, we studied five additional subjects and found that these patients were consistent with the previously defined archetypal clusters of clinical and anatomical characteristics. Secondary analysis of five subjects with related diagnoses showed that disease groups that were clinically and pathophysiologically similar also shared similar anatomic characteristics. Specifically, Archetype #1 consisted of SCA3 (n=1) and SCA2, suggesting that cerebellar syndromes accompanied by atrophy of the pons may be associated with a characteristic pattern of cerebellar neurodegeneration. In comparison, Archetype #2 was comprised of disease groups with pure cerebellar atrophy (episodic ataxia type 2 (n=1), idiopathic late-onset cerebellar ataxias (n=3), and SCA6). This suggests that cerebellar shape analysis could aid in discriminating between different pathologies. Our findings further suggest that magnetic resonance imaging is a promising imaging biomarker that could aid in the diagnosis and therapeutic management in patients with cerebellar syndromes.
doi:10.1007/s12311-011-0334-6
PMCID: PMC3932524  PMID: 22258915
Ataxia; Magnetic resonance imaging (MRI); Principal component analysis (PCA); Cerebellum; Biomarker
9.  DEFORMABLE REGISTRATION OF MACULAR OCT USING A-MODE SCAN SIMILARITY 
Optical coherence tomography (OCT) of the macular cube has become an increasingly important tool for investigating and managing retinal pathology. One important new area of investigation is the analysis of anatomic variably across a population. Such an analysis on the retina requires the construction of a normalized space, which is generally created through deformable registration of each subject into a common template. Unfortunately, state-of-the-art 3D registration tools fail to adequately spatially normalize retinal OCT images. This work proposes a new deformable registration algorithm for OCT images using the similarity between pairs of A-mode scans. First, a retinal OCT specific affine step is presented, which uses automated landmarks to perform global translations and individual rescaling of all the subject’s A-mode scans. Then, a deformable registration using regularized one-dimensional radial basis functions is applied to further align the retinal layers. Results on 15 subjects show the improved accuracy of this approach in comparison to state of the art methods with respect to registration for labeling. Additional results show the ability to generate stereotaxic spaces for retinal OCT.
doi:10.1109/ISBI.2013.6556515
PMCID: PMC3892764  PMID: 24443687
Optical coherence tomography; registration
10.  Vertical Vergence Adaptation Produces an Objective Vertical Deviation That Changes With Head Tilt 
Purpose.
To document the cyclovertical ocular motor mechanism used for vertical fusion in healthy subjects, and to explore whether vertical vergence training in healthy individuals can produce objectively confirmed vertical deviations that change with head tilt, revealing a basic mechanism that can produce a pattern of misalignment in an otherwise normal ocular motor system that is similar to superior oblique muscle paresis (SOP).
Methods.
Seven subjects with normal orthoptic examinations were adapted to vertical image disparities using our tilting haploscopic eye-tracking apparatus presenting concentric circle targets without torsional cues. Static eye positions were recorded with head straight and when tilted 45 degrees to the left and right, during both binocular and monocular viewing.
Results.
Vertical fusional vergence was accompanied by a cycloversion, with the downward-moving eye intorting and the upward-moving eye extorting, implicating primary involvement of the oblique extraocular muscles. After adaptation to the slowly increasing vertical target separation, all subjects developed a temporary vertical deviation in the straight ahead position that increased with head tilt to one side and decreased with head tilt to the other side.
Conclusions.
These results not only show that head-tilt–dependent changes in vertical deviation are not necessarily pathognomonic for SOP, but also, and more importantly, suggest mechanisms that can mimic SOP and suggest a possible role for vertical vergence training in reducing deviations and thus the amount of head tilt required for fusion. Ultimately, vertical vergence training may provide an adjunct or alternative to extraocular muscle surgery in selected cases.
Vertical vergence training in healthy individuals can produce an objective vertical deviation that changes with different head tilt positions, revealing a basic mechanism that can produce head tilt findings similar to those in superior oblique paresis in an otherwise normal ocular motor system.
doi:10.1167/iovs.12-11368
PMCID: PMC3645368  PMID: 23572100
vertical vergence adaptation; superior oblique paresis; Bielschowsky head tilt test; basic cyclovertical deviation; video-oculography
11.  MRI shows a region-specific pattern of atrophy in spinocerebellar ataxia type 2 
Cerebellum (London, England)  2012;11(1):272-279.
In this study, we used manual delineation of high-resolution magnetic resonance imaging (MRI) to determine the spatial and temporal characteristics of the cerebellar atrophy in spinocerebellar ataxia type 2 (SCA2). Ten subjects with SCA2 were compared to ten controls. The volume of the pons, the total cerebellum, and the individual cerebellar lobules were calculated via manual delineation of structural MRI. SCA2 showed substantial global atrophy of the cerebellum. Furthermore, the degeneration was lobule-specific, selectively affecting the anterior lobe, VI, Crus I, Crus II, VIII, uvula, corpus medullare, and pons, while sparing VIIB, tonsil/paraflocculus, flocculus, declive, tuber/folium, pyramis, and nodulus. The temporal characteristics differed in each cerebellar subregion: 1) Duration of disease: Crus I, VIIB, VIII, uvula, corpus medullare, pons, and the total cerebellar volume correlated with the duration of disease; 2) Age: VI, Crus II, and flocculus correlated with age in control subjects; 3) Clinical scores: VI, Crus I, VIIB, VIII, corpus medullare, pons, and the total cerebellar volume correlated with clinical scores in SCA2. No correlations were found with the age of onset. Our extrapolated volumes at the onset of symptoms suggest that neurodegeneration may be present even during the presymptomatic stages of disease. The spatial and temporal characteristics of the cerebellar degeneration in SCA2 are region-specific. Furthermore, our findings suggest the presence of presymptomatic atrophy and a possible developmental component to the mechanisms of pathogenesis underlying SCA2. Our findings further suggest that volumetric analysis may aid in the development of a non-invasive, quantitative biomarker.
doi:10.1007/s12311-011-0308-8
PMCID: PMC3785794  PMID: 21850525
ataxia; spinocerebellar ataxia type 2 (SCA2); magnetic resonance imaging (MRI); biomarker
12.  Retinal layer segmentation of macular OCT images using boundary classification 
Biomedical Optics Express  2013;4(7):1133-1152.
Optical coherence tomography (OCT) has proven to be an essential imaging modality for ophthalmology and is proving to be very important in neurology. OCT enables high resolution imaging of the retina, both at the optic nerve head and the macula. Macular retinal layer thicknesses provide useful diagnostic information and have been shown to correlate well with measures of disease severity in several diseases. Since manual segmentation of these layers is time consuming and prone to bias, automatic segmentation methods are critical for full utilization of this technology. In this work, we build a random forest classifier to segment eight retinal layers in macular cube images acquired by OCT. The random forest classifier learns the boundary pixels between layers, producing an accurate probability map for each boundary, which is then processed to finalize the boundaries. Using this algorithm, we can accurately segment the entire retina contained in the macular cube to an accuracy of at least 4.3 microns for any of the nine boundaries. Experiments were carried out on both healthy and multiple sclerosis subjects, with no difference in the accuracy of our algorithm found between the groups.
doi:10.1364/BOE.4.001133
PMCID: PMC3704094  PMID: 23847738
(100.0100) Image processing; (170.4470) Ophthalmology; (170.4500) Optical coherence tomography
13.  The nonlinearity of passive extraocular muscles 
Passive extraocular muscles (EOMs), like most biological tissues, are hyper-elastic, i.e., their stiffness increases as they are stretched. It has always been assumed, and in a few occasions argued, that this is their only nonlinearity and that it can be ignored in central gaze. However, using novel measurement techniques in anesthetized paralyzed monkeys, we have recently demonstrated that EOMs are characterized by another prominent nonlinearity: the forces induced by sequences of stretches do not sum. Thus, superposition, a central tenet of linear and quasi-linear models, does not hold in passive EOMs. Here, we outline the implications of this finding, especially in light of the common assumption that it is easier for the brain to control a linear than a nonlinear plant. We argue against this common belief: the specific nonlinearity of passive EOMs may actually make it easier for the brain to control the plant than if muscles were linear.
doi:10.1111/j.1749-6632.2011.06111.x
PMCID: PMC3187914  PMID: 21950971
viscoelasticity; model; control; quasilinear; superposition
14.  Contact focusing multimodal microprobes for ultraprecise laser tissue surgery 
Optics Express  2011;19(4):3440-3448.
Focusing of multimodal beams by chains of dielectric microspheres assembled directly inside the cores of hollow waveguides is studied by using numerical ray tracing. The device designs are optimized for laser surgery in contact mode with strongly absorbing tissue. By analyzing a broad range of parameters it is demonstrated that chains formed by three or five spheres with a refractive index of 1.65-1.75 provide a two-fold improvement in spatial resolution over single spheres at the cost of 0.2-0.4 attenuation in peak intensity of the central focused beam. Potential applications include ultra precise laser ablation or coagulation in the eye and brain, cellular surgery, and the coupling of light into photonic nanostructures.
doi:10.1364/OE.19.003440
PMCID: PMC3368307  PMID: 21369166
(170.3890) Medical optics instrumentation; (170.4460) Ophthalmic optics and devices; (230.3990) Micro-optical devices; (220.2740) Geometrical optics design
15.  Do Palisade Endings in Extraocular Muscles Arise from Neurons in the Motor Nuclei? 
The data in this study, obtained from tract-tracing experiments in the monkey, imply that the palisade endings located at the myotendinous junction of eye muscles arise from the motor nuclei in the brain stem.
Purpose.
The purpose of this study was to localize the cell bodies of palisade endings that are associated with the myotendinous junctions of the extraocular muscles.
Methods.
Rhesus monkeys received tract-tracer injections (tetramethylrhodamine dextran [TMR-DA] or choleratoxin subunit B [CTB]) into the oculomotor and trochlear nuclei, which contain the motoneurons of extraocular muscles. All extraocular muscles were processed for the combined immunocytochemical detection of the tracer and SNAP-25 or synaptophysin for the visualization of the complete muscle innervation.
Results.
In all muscles—except the lateral rectus—en plaque and en grappe motor endings, but also palisade endings, were anterogradely labeled. In addition a few tracer-labeled tendon organs were found. One group of tracer-negative nerve fibers was identified as thin tyrosine hydroxylase-positive sympathetic fibers, and a second less numerous group of tracer-negative fibers may originate from the trigeminal ganglia. No cellular or terminal tracer labeling was present within the mesencephalic trigeminal nucleus or the trigeminal ganglia.
Conclusions.
These results confirm those of earlier studies and furthermore suggest that the somata of palisade endings are located close to the extraocular motor nuclei—in this case, probably within the C and S groups around the periphery of the oculomotor nucleus. The multiple en grappe endings have also been shown to arise from these cells groups, but it is not possible to distinguish different populations in these experiments.
doi:10.1167/iovs.10-6008
PMCID: PMC3088547  PMID: 21228383
16.  Effects of Intracranial Trochlear Neurectomy on the Structure of the Primate Superior Oblique Muscle 
The diagnosis of superior oblique palsy is commonly invoked to explain acquired diplopia, but the clinical features of this form of cyclovertical strabismus are inconsistent and poorly understood. The primate model of acquired superior oblique palsy reported in this article provides surprising anatomic insights into the selective response of extraocular muscle layers to denervation and sheds light on some mysterious aspects of human superior oblique palsy.
Purpose.
Although cyclovertical strabismus in humans is frequently attributed to superior oblique (SO) palsy, anatomic effects of SO denervation have not been studied. Magnetic resonance imaging (MRI) and orbital histology was used to study the effects of acute trochlear (CN4) denervation on the monkey SO.
Methods.
Five juvenile macaque monkeys were perfused with formalin for 5 weeks: 15 months after unilateral or bilateral 10-mm intracranial trochlear neurectomy. Denervated and fellow orbits were imaged by MRI, embedded whole in paraffin, serially sectioned at 10-μm thickness, and stained with Masson trichrome. Whole muscle and individual fiber cross sections were quantified in SO muscles throughout the orbit and traced larger fibers in one specimen where they were present.
Results.
MRI demonstrated marked reduction in midorbital cross section in denervated SO muscles, with anterior shift of SO mass preserving overall volume. Muscle fibers exhibited variable atrophy along their lengths. Denervated orbital layer (OL) fiber cross sections were slightly but significantly reduced from control at most anteroposterior locations, but this reduction was much more profound in global layer (GL) fibers. Intraorbital and intramuscular CN4 were uniformly fibrotic. In one animal, there were scattered clusters of markedly hypertrophic GL fibers that exhibited only sparse myomyous junctions only anteriorly.
Conclusions.
CN4 denervation produces predominantly SO GL atrophy with relative OL sparing. Overall midorbital SO atrophy was evident by MRI as early as 5 weeks after denervation, as denervated SO volume shifted anteriorly. Occasional GL fiber hypertrophy suggests that at least some SO fibers extend essentially the full muscle length after trochlear neurectomy.
doi:10.1167/iovs.09-5120
PMCID: PMC2904006  PMID: 20164458
17.  The Cerebellar Nodulus/Uvula Integrates Otolith Signals for the Translational Vestibulo-Ocular Reflex 
PLoS ONE  2010;5(11):e13981.
Background
The otolith-driven translational vestibulo-ocular reflex (tVOR) generates compensatory eye movements to linear head accelerations. Studies in humans indicate that the cerebellum plays a critical role in the neural control of the tVOR, but little is known about mechanisms of this control or the functions of specific cerebellar structures. Here, we chose to investigate the contribution of the nodulus and uvula, which have been shown by prior studies to be involved in the processing of otolith signals in other contexts.
Methodology/Principal Findings
We recorded eye movements in two rhesus monkeys during steps of linear motion along the interaural axis before and after surgical lesions of the cerebellar uvula and nodulus. The lesions strikingly reduced eye velocity during constant-velocity motion but had only a small effect on the response to initial head acceleration. We fit eye velocity to a linear combination of head acceleration and velocity and to a dynamic mathematical model of the tVOR that incorporated a specific integrator of head acceleration. Based on parameter optimization, the lesion decreased the gain of the pathway containing this new integrator by 62%. The component of eye velocity that depended directly on head acceleration changed little (gain decrease of 13%). In a final set of simulations, we compared our data to the predictions of previous models of the tVOR, none of which could account for our experimental findings.
Conclusions/ Significance
Our results provide new and important information regarding the neural control of the tVOR. Specifically, they point to a key role for the cerebellar nodulus and uvula in the mathematical integration of afferent linear head acceleration signals. This function is likely to be critical not only for the tVOR but also for the otolith-mediated reflexes that control posture and balance.
doi:10.1371/journal.pone.0013981
PMCID: PMC2981566  PMID: 21085587
18.  The Viscoelastic Properties of Passive Eye Muscle in Primates. III: Force Elicited by Natural Elongations 
PLoS ONE  2010;5(3):e9595.
We have recently shown that in monkey passive extraocular muscles the force induced by a stretch does not depend on the entire length history, but to a great extent is only a function of the last elongation applied. This led us to conclude that Fung's quasi-linear viscoelastic (QLV) model, and more general nonlinear models based on a single convolution integral, cannot faithfully mimic passive eye muscles. Here we present additional data about the mechanical properties of passive eye muscles in deeply anesthetized monkeys. We show that, in addition to the aforementioned failures, previous models also grossly overestimate the force exerted by passive eye muscles during smooth elongations similar to those experienced during normal eye movements. Importantly, we also show that the force exerted by a muscle following an elongation is largely independent of the elongation itself, and it is mostly determined by the final muscle length. These additional findings conclusively rule out the use of classical viscoelastic models to mimic the mechanical properties of passive eye muscles. We describe here a new model that extends previous ones using principles derived from research on thixotropic materials. This model is able to account reasonably well for our data, and could thus be incorporated into models of the eye plant.
doi:10.1371/journal.pone.0009595
PMCID: PMC2833209  PMID: 20221406
19.  Enhancement of the Bias Component of Downbeat Nystagmus after Lesions of the Nodulus and Uvula 
In two monkeys, we recorded spontaneous eye movements before and after ablation of the cerebellar nodulus and uvula (Nod/Uv). In both monkeys, there was an increase in upward ocular drift (downbeat nystagmus, DBN) in darkness (M1: 1.5 °/s pre, 3.4 °/s post; M2: 1.3 °/s pre, 7.0 °/s post), but not in light. There was little effect of orbital position on drift velocity. These findings suggest that the Nod/Uv may play a role in the bias component of DBN.
doi:10.1111/j.1749-6632.2008.03717.x
PMCID: PMC2758645  PMID: 19645954
Cerebellum; Rhesus; Monkey; Ataxia; Oscillopsia
20.  The Viscoelastic Properties of Passive Eye Muscle in Primates. II: Testing the Quasi-Linear Theory 
PLoS ONE  2009;4(8):e6480.
We have extensively investigated the mechanical properties of passive eye muscles, in vivo, in anesthetized and paralyzed monkeys. The complexity inherent in rheological measurements makes it desirable to present the results in terms of a mathematical model. Because Fung's quasi-linear viscoelastic (QLV) model has been particularly successful in capturing the viscoelastic properties of passive biological tissues, here we analyze this dataset within the framework of Fung's theory.
We found that the basic properties assumed under the QLV theory (separability and superposition) are not typical of passive eye muscles. We show that some recent extensions of Fung's model can deal successfully with the lack of separability, but fail to reproduce the deviation from superposition.
While appealing for their elegance, the QLV model and its descendants are not able to capture the complex mechanical properties of passive eye muscles. In particular, our measurements suggest that in a passive extraocular muscle the force does not depend on the entire length history, but to a great extent is only a function of the last elongation to which it has been subjected. It is currently unknown whether other passive biological tissues behave similarly.
doi:10.1371/journal.pone.0006480
PMCID: PMC2715107  PMID: 19649257
21.  Lesions of the Cerebellar Nodulus and Uvula in Monkeys: Effect on Otolith-Ocular Reflexes 
Progress in brain research  2008;171:167-172.
We studied two rhesus monkeys before and after surgical ablation of the nodulus and uvula (Nod/Uv) of the cerebellum. Three-axis eye movements were recorded with the magnetic-field scleral search coil system during a variety of vestibular and ocular motor tasks. Here we describe the effects of the Nod/Uv lesions on dynamic (head translation) and static (head tilt) otolith-mediated vestibulo-ocular reflexes. The main findings were: 1) eye velocity during sinusoidal vertical translation (1.5 Hz) was reduced by 59% in the dark and 36% in the light; 2) eye velocity during steps of horizontal translation was reduced, but only in the dark and more so during the sustained (constant-velocity) than the initial (acceleration) part of the response, and 3) there was a torsional nystagmus that depended on the position of roll head tilt, but static ocular counterroll was unchanged. These results suggest new roles for the Nod/Uv in the processing of otolith signals. This is likely important not only for facilitating gaze during linear head motion, but also for maintaining postural stability and one’s orientation relative to gravity. The lesions appeared to have a greater effect on responses to vertical motion, particularly in the light (in contrast responses to interaural translation in the light were nearly normal), suggesting a particular importance of the Nod/Uv in processing signals arising from the sacculi.
doi:10.1016/S0079-6123(08)00622-5
PMCID: PMC2718056  PMID: 18718296
22.  The Effect of Acute Superior Oblique Palsy on Torsional Optokinetic Nystagmus in Monkeys 
Purpose
To investigate the effects of acquired superior oblique palsy (SOP) and corrective strabismus surgery on torsional optokinetic nystagmus (tOKN) in monkeys.
Methods
The trochlear nerve was severed intracranially in two rhesus monkeys (M1 and M2). For each monkey, more than 4 months after the SOP, the ipsilateral inferior oblique muscle was denervated and extirpated. For M2, 4 months later, the contralateral inferior rectus muscle was recessed by 2 mm. tOKN was elicited during monocular viewing of a rotating stimulus that was rear projected onto a screen 43.5 cm in front of the animal. Angular rotation of the stimulus about the center was 40 deg/s clockwise or counterclockwise.
Results
The main findings after trochlear nerve sectioning were (1) the amplitude and peak velocity of torsional quick and slow phases of the paretic eye was less than that in the normal eye for both intorsion and extorsion, and (2) the vertical motion of the paretic eye increased during both torsional slow and quick phases. After corrective inferior oblique surgery, both of these effects were even greater.
Conclusions
Acquired SOP and corrective inferior oblique–weakening surgery create characteristic patterns of change in tOKN that reflect alterations in the dynamic properties of the extraocular muscles involved in eye torsion. tOKN also provides information complementary to that provided by the traditional Bielschowsky head-tilt test and potentially can help distinguish among different causes of vertical ocular misalignment.
doi:10.1167/iovs.07-0989
PMCID: PMC2367221  PMID: 18385059
23.  The Viscoelastic Properties of Passive Eye Muscle in Primates. I: Static Forces and Step Responses 
PLoS ONE  2009;4(4):e4850.
The viscoelastic properties of passive eye muscles are prime determinants of the deficits observed following eye muscle paralysis, the root cause of several types of strabismus. Our limited knowledge about such properties is hindering the ability of eye plant models to assist in formulating a patient's diagnosis and prognosis. To investigate these properties we conducted an extensive in vivo study of the mechanics of passive eye muscles in deeply anesthetized and paralyzed monkeys. We describe here the static length-tension relationship and the transient forces elicited by small step-like elongations. We found that the static force increases nonlinearly with length, as previously shown. As expected, an elongation step induces a fast rise in force, followed by a prolonged decay. The time course of the decay is however considerably more complex than previously thought, indicating the presence of several relaxation processes, with time constants ranging from 1 ms to at least 40 s. The mechanical properties of passive eye muscles are thus similar to those of many other biological passive tissues. Eye plant models, which for lack of data had to rely on (erroneous) assumptions, will have to be updated to incorporate these properties.
doi:10.1371/journal.pone.0004850
PMCID: PMC2660417  PMID: 19337381

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