Project

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Study of infantile nystagmus syndrome: development of the ocular motor system, disease mechanism and clinical applications

Applicant Huang Melody Ying-Yu
Number 139754
Funding scheme Marie Heim-Voegtlin grants
Research institution Universitätsspital Zürich, Neurologie
Institution of higher education University of Zurich - ZH
Main discipline Neurology, Psychiatry
Start/End 01.02.2012 - 31.05.2014
Approved amount 251'434.00
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All Disciplines (2)

Discipline
Neurology, Psychiatry
Neurophysiology and Brain Research

Keywords (8)

Infantile nystagmus syndrome (INS); Optokinetic response (OKR); Visual pathway abnormality; Ocular motor system; Vestibulo-ocular reflex (VOR); Albinism; Congenital nystagmus (CN); Zebrafish

Lay Summary (English)

Lead
Infantile nystagmus syndrome (INS), with so far unknown etiology, is associated with a broad range of visual system deficits. Strong resemblance between ocular motor instabilities in achiasmatic zebrafish and in infantile INS patients leads to the hypothesis that visual pathway abnormality may also be a key factor in human INS.
Lay summary

BACKGROUND: Infantile nystagmus syndrome (INS) is an eye movement disorder characterized by horizontally oscillating eyes. The long-term goal of this project is to expand our knowledge of INS, propose new treatment avenues for INS, and increase our understanding of the ocular motor systems in vertebrates in general. INS is frequently associated with abnormalities in the visual system, for example as present in albinism. We found a zebrafish mutant, called belladonna, that shows horizontally oscillating eyes and an underlying condition of abnormally projecting optic pathways. Our previous data demonstrate that the underlying condition is directly responsible for the oscillating eyes. We hypothesize that abnormally projecting optic pathways may similarly contribute to the eye oscillations in human INS, at least in those patients where such a condition is present.

AIMS: (1) We plan to mimic the effect of abnormally projecting optic pathways in healthy humans with a specially designed experimental setup (the movement of a visual scene is yoked to the eye movement). We anticipate that, under this condition, healthy subjects show eye movements that are similar to those in INS. Conversely, eye oscillations in INS patients are expected to be reduced under this condition. (2) In INS patients, different eye movement systems (e.g., optokinetic and vestibulo-ocular system) are known to be compromised. We will test how the performance of different eye movement systems is altered in zebrafish mutant belladonna through the early development. (3) Abnormalities in the projection of the optic pathways are possibly expressed in different types of eye oscillations. Taking advantage of the correlation between visual pathway configuration and eye movements, we plan to develop a diagnostic algorithm to screen for aberrant visual pathways solely based on eye movement recordings. Additionally, we will test optical and other treatment methods. Finally, we will use zebrafish mutant belladonna to screen for potential new drugs and test existing neurological drugs that have not yet been tested in INS patients.

IMPORTANCE AND IMPACT: The aim of this project is to identify the underlying (developmental) cause of INS and to generally expand our knowledge of the optokinetic system in zebrafish and human. These insights will help better understand and diagnose INS and eventually improve the treatment.

Direct link to Lay Summary Last update: 19.07.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Afternystagmus in darkness after suppression of optokinetic nystagmus: an ocular motor response to a motion aftereffect driven by retinal afterimages
Chen Chien-Cheng, Huang Melody Ying-Yu, Weber Konrad P., Straumann Dominik, Bockisch Christopher J. (2014), Afternystagmus in darkness after suppression of optokinetic nystagmus: an ocular motor response to a motion aftereffect driven by retinal afterimages, in Experimental Brain Research, 1-8.
Individual Larvae of the Zebrafish Mutant belladonna Display Multiple Infantile Nystagmus-Like Waveforms that Are Influenced by Viewing Conditions
Huber-Reggi Sabina P., Mueller Kaspar P., Straumann Dominik, Huang Melody Ying-Yu, Neuhauss Stephan C. F. (2014), Individual Larvae of the Zebrafish Mutant belladonna Display Multiple Infantile Nystagmus-Like Waveforms that Are Influenced by Viewing Conditions, in Investigative Ophthalmology & Visual Science, 55(6), 3971-3978.
Positive or Negative Feedback of Optokinetic Signals: Degree of the Misrouted Optic Flow Determines System Dynamics of Human Ocular Motor Behavior
Chen Chien-Cheng, Bockisch Christopher J., Olasagasti Itsaso, Weber Konrad P., Straumann Dominik, Huang Melody Ying-Yu (2014), Positive or Negative Feedback of Optokinetic Signals: Degree of the Misrouted Optic Flow Determines System Dynamics of Human Ocular Motor Behavior, in Investigative Ophthalmology & Visual Science, 55(4), 2297-2306.
Velocity storage mechanism in zebrafish larvae
Chen Chien-Cheng, Bockisch Christopher, Bertolini Giovanni, Olasagasti Itsaso, Neuhauss Stephan, Weber Konrad, Straumann Dominik, Huang Melody Ying-Yu (2014), Velocity storage mechanism in zebrafish larvae, in The Journal of Physiology, 592(1), 203-214.
Albino mice as an animal model for infantile nystagmus syndrome.
Traber Ghislaine L, Chen Chien-Cheng, Huang Ying-Yu, Spoor Marcella, Roos Jeanine, Frens Maarten A, Straumann Dominik, Grimm Christian (2012), Albino mice as an animal model for infantile nystagmus syndrome., in Investigative ophthalmology & visual science, 53(9), 5737-47.
Severity of infantile nystagmus syndrome-like ocular motor phenotype is linked to the extent of the underlying optic nerve projection defect in zebrafish belladonna mutant.
Huber-Reggi Sabina P, Chen Chien-Cheng, Grimm Lea, Straumann Dominik, Neuhauss Stephan C F, Huang Melody Ying-Yu (2012), Severity of infantile nystagmus syndrome-like ocular motor phenotype is linked to the extent of the underlying optic nerve projection defect in zebrafish belladonna mutant., in The Journal of neuroscience : the official journal of the Society for Neuroscience, 32(50), 18079-86.

Collaboration

Group / person Country
Types of collaboration
University of Pavia Italy (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
Neuropsychologie, UniversitätsSpital Zürich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Universitätsspital Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Inselspital Bern Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Johns Hopkins Hospital United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
LMU München Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Psychiatric University Clinic of Zurich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
43rd Annual Meeting, Society for Neuroscience (SfN) Poster Velocity storage mechanism in zebrafish larvae 09.11.2013 San Diego, CA, United States of America Huang Melody Ying-Yu;
3rd International Nystagmus Research Workshop Individual talk Mechanisms of infantile nystagmus syndrome in human and fish 05.09.2013 Abingdon, England, Great Britain and Northern Ireland Huang Melody Ying-Yu;
Gordon Research Conferences- Eye Movements: The Motor System that Sees the World Individual talk Doomed to move the eyes: Nystagmus in fish and men 07.07.2013 Easton, MA, United States of America Huang Melody Ying-Yu;
The Vestibular System – A Clinical and Scientific Update in Siena Poster Dancing eyes: The positive optokinetic feedback loop 04.04.2013 Siena, Italy Huang Melody Ying-Yu;
42nd Annual Meeting, Society for Neuroscience (SfN) Poster Dancing eyes: The positive optokinetic feedback loop 13.10.2012 New Orleans, United States of America Huang Melody Ying-Yu;


Associated projects

Number Title Start Funding scheme
118069 Three-dimensional kinematical analysis of ocular motor disorders in humans 01.10.2007 Project funding (Div. I-III)

Abstract

To date, the pathomechanism of infantile nystagmus syndrome (INS), an ocular motor disorder characterized by involuntary horizontal eye oscillations, is unknown. My discovery of achiasmatic zebrafish belladonna (bel) mutant with an INS-like behavioral phenotype promises new insights into the etiology of INS. Just like in achiasmatic zebrafish bel mutant, visual pathway abnormalities are commonly present in INS patients and may, therefore, be a factor in the pathogenesis of INS. To substantiate this hypothesis, I will measure the ocular motor behavior of normals and subjects with INS when exposed to an artificially generated inverted retinal slip. To understand the role of the vestibulo-ocular reflex (VOR) in INS, I will examine the development of the VOR in achiasmatic zebrafish bel mutant. I will use achiasmatic zebrafish bel mutant to evaluate and discover new pharmacological treatments for INS. Finally, I plan to develop a new diagnostic method for visual pathway abnormalities.
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