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Visual Neurosciences Research Group


Overview

The Visual Neurosciences Research Group is interested in neurobiological interactions between the visual system and the brain with the aim of translating fundamental scientific knowledge into screening and therapeutic interventions used in clinical settings. More specifically, our group of ophthalmologists, neuroscientists, molecular biologists and biomedical engineers are investigating the behavioral and physiological consequences of clinical conditions affecting the retina and the optic nerve. These conditions include glaucoma and diabetic retinopathy, as well as other inflammatory, compressive, hereditary optic neuropathies. Through various local and international collaborations, our group is also studying the impact of light on ocular growth and metabolomics in different animal models of myopia.


1. Dysfunction of the intrinsically photosensitive retinal ganglion cells and screening devices in ophthalmic conditions.
Early work from our group has shown dysfunction in the melanopsin expressing retinal ganglion cells (mRGCs) system in primary open angle glaucoma. This dysfunction, assessed using chromatic pupillometry, is evident in the earliest stages of glaucoma and correlates with the severity of the disease. In collaboration with the Glaucoma group at SERI, we are currently evaluating the efficiency of a novel chromatic pupillometry paradigm delivered using a dedicated pupillometer for detecting early glaucoma and other ocular and neurodegenerative diseases. We also aim to assess the functions of the intrinsically photosensitive retinal ganglion cells in other neurodegenerative and inflammatory conditions that affect the visual pathways and central nervous system (i.e. Alzheimer’s disease [AD], Parkinson’s disease [PD] and Multiple sclerosis).


2. The neurobiology of photic interventions for myopia prevention. Myopia is the leading cause of visual impairment worldwide.
Besides its direct socio-economic burden, especially in Singapore (USD 755 million annually), myopia is associated with vision threatening ocular complications, such as glaucoma, retinal detachment, and neovascularisation. Increased time spent outdoors has recently been singled out as preventive against myopia. The protective effect of time spent outdoors could be due to the increased brightness and unique spectral characteristics of sunlight that are generally lacking indoors. In collaboration with local (the Myopia group and the Translational Preclinical Model Platform at SERI) and international collaborators (Biochemistry and Genetics Lab, CHU Angers, France), our group is currently exploring the neurobiology underlying the impact of spectral and temporal tuning of artificial light on myopia development and progression in different animal models of myopia. 


3. Hereditary optic neuropathies.
Our group has recently identified patients with genetically confirmed Autosomal Dominant Optic Atrophy in Singapore, a condition which is only rarely reported in South-East Asia. Collaborations with a group of geneticists in Angers, France, have enabled us to identify novel genetic mutations in the OPA1 gene, responsible not only for visual loss due to optic atrophy, but also deafness. Various other mitochondrial genetic mutations affecting the optic nerves are being explored through our collaboration with a team of geneticists in Angers, France, led by Professor Reynier and Professor Procaccio.


4. Ocular motor dysfunctions associated with neurodegenerative diseases.
Amongst other deficiencies, neurodegenerative diseases are associated with various ocular motor defects. In AD for example, these alterations involve the inhibitory oculo-motor and anticipatory pursuit processes, as well as smooth saccadic eye movement and slow pursuit. Various eye movement paradigms have been used to detect distinct memory and cognitive impairments associated with neuronal degeneration. Recent behavioral and neuroimaging findings have also brought significant neuroscientific insight into the study of pupil functions. Classically, the pupils can provide information about the integrity of the afferent visual system, but also the efferent sympathetic and parasympathetic system in health and disease. Novel areas in neuroscience and neuropsychology have shown that pupil size can also vary in various conditions of emotional and cognitive load and in response to illusions of brightness. Such pupillary changes are dependent upon the integrity of the cortical system, an integrity that is affected in numerous disease states influencing cognition and mood. Our group is studying and developing novel approaches combining eye movements and pupillary features to better understand the pathophysiology and identify novel behavioral biomarkers of neurodegenerative conditions, like AD and PD.   


Publications

  1. Najjar RP, Mack H, Milea D. Retinal Neuronal Loss in Visually Asymptomatic Patients with Myoclonic Epilepsy with Ragged-Red Fibers. J. Neuro-Ophthalmol, 2018, in press.

  2. Faroqui S, Chan A, Cullen B, Milea D. Too young to undergo temporal artery biopsy? Calciphylaxis-related anterior ischemic optic neuropathy. Neuro-Ophthalmology, 2018, in press.

  3. Chiambaretta F, Pleyer U, Behndig A, Pisella PJ, Mertens E, Limao A, Fasce F, Fernandez J, Benmoussa SE, Labetoulle M, Cochener B, Intracameral Mydrane (ICMA) and Ethics Group. Pupil dilation dynamics with an intracameral fixed combination of mydriatics and anesthetic during cataract surgery. J Cataract Refract Surg. 2018 Mar;44(3):341-347

  4. Ebran JM, Martin L, Leftheriotis, Navasiolava N, Ferre M, Milea D, Leruez S. Subretinal fibrosis is associated with fundus pulverulentus in pseudoxanthoma elasticum. Graefes Arch Clin Exp Ophthalmol. 2018 Apr;256(4):699-707. https://dx.doi.org/10.1016/j.jcrs.2017.12.025

  5. Zeitzer JM, Najjar RP, Wang C-A, Kass M. Impact of blue-depleted white light on pupil dynamics, melatonin suppression and subjective alertness following real-world light exposure. Sleep Science and Practice, 2018, 2:1. https://doi.org/10.1186/s41606-018-0022-2

  6. Najjar RP, Sharma S, Atalay E, Rukmini AV, Sun C, Lock JZ, Baskaran M, Perera S, Hussain R, Lamoureux E, Gooley JJ, Aung T, PhD, Milea D. Pupillary responses to full-field chromatic stimuli are reduced in patients with early-stage primary open-angle glaucoma. Ophthalmology, 2018, (e-pub ahead of print). https://doi.org/10.1016/j.ophtha.2018.02.024

  7. Leruez S, Bresson T, Chao de la Barca JM, Marill A, de Saint Martin G, Buisset A, Muller J, Tessier L, Gadras C, Verny C, Amati-Bonneau P, Lenaers G, Gohier P, Bonneau D, Simard G, Milea D, Procaccio V, Reynier P. A plasma metabolomic signature of the exfoliation syndrome involves amino acids, acyl-carnitines and polyamines. Investigative Ophthalmology and Visual Science. 2018, in press.

  8. Leruez S, Verny C, Bonneau D, Procaccio V, Lenaers G, Amati-Bonneau P, Reynier P, Scherer C, Prundean A, Orssaud C, Zanlonghi X, Rougier MB, Tilikete C, Milea D. Cyclosporine A does not prevent second-eye involvement in Leber's hereditary optic neuropathy. Orphanet Journal of Rare Diseases, 2018, Feb 17;13(1):33. https://dx.doi.org/10.1186/s13023-018-0773-y

  9. Najjar RP, Zeitzer JM. Anatomy and Physiology of the Circadian System. In: Miglis MG, ed. Sleep and Neurologic Disease. San Diego: Academic Press; 2017:29–53. https://www.sciencedirect.com/science/article/pii/B9780128040744000029

  10. Bocca C, Kouassi Nzoughet J, Leruez S, Amati-Bonneau P, Ferré M, Kane MS, Veyrat-Durebex C, Chao de la Barca JM, Chevrollier A, Homedan C, Verny C, MilEa D, Procaccio V, Simard G, Bonneau D, Lenaers G, Reynier P. A Plasma Metabolomic Signature Involving Purine Metabolism in Human Optic Atrophy 1 (OPA1)-Related Disorders. Invest Ophthalmol Vis Sci. 2018 Jan 1;59(1):185-195. https://dx.doi.org/10.1167/iovs.17-23027

  11. Sharma S, Tun TA, Baskaran M, Atalay E, Thakku SG, Liang Z, Milea D, Strouthidis NG, Aung T, Girard MJ. Effect of intraocular pressure elevation on the minimum rim width in normal, ocular hypertensive and glaucoma eyes. Br J Ophthalmol, 2018 Jan;102(1):131-135. https://dx.doi.org/10.1136/bjophthalmol-2017-310232

  12. Tan ACS, Tan GS, Denniston AK, Keane PA, Ang M, Milea D, Chakravarthy U, Cheung CMG. An overview of the clinical applications of optical coherence tomography angiography. Eye (London), 2018, Sept 8. https://dx.doi.org/ 10.1038/eye.2017.181

  13. Teo KY, Tow SL, Haaland B, Gosavi TD, Loo JL, Lo YL, Milea D. Low conversion rate of ocular to generalized myasthenia gravis in Singapore. Muscle Nerve. 2018 May;57(5):756-760. https://dx.doi.org/ 10.1002/mus.25983

  14. Sharma S, Ang M, Najjar RP, Sng C, Cheung C, Milea D. Optical coherence tomography angiography in acute non-arteritic anterior ischemic optic neuropathy. Br J Ophthalmol. 2017 Aug;101(8):1045-1051. https://dx.doi.org/10.1136/bjophthalmol-2016-309245

  15. Rukmini AV, Najjar RP, Atalay RP, Sharma S, MD, Lock JZ, Mani B, Nongpiur M, Aung T, Milea D. Pupillary responses to light are not affected by narrow irido-corneal angles.  Sci Rep, 2017, 31(7): 10190 . https://dx.doi.org/10.1038/s41598-017-10303-3

  16. Aung T, Ozaki M, …Milea D, …., Pasutto F, Khor CC. Worldwide genetic association study of exfoliation syndrome identifies highly protective rare mutations at LOXL1 and five new common-variant susceptibility loci. Nature Genetics, 2017, Jul;49(7):993-1004. https://dx.doi.org/ 10.1038/ng.3875

  17. Lo YL, Najjar RP, Milea D. Diagnostic tests for myasthenia gravis with ocular involvement. J Neurol Sci. 2017 Aug 15;379:338. https://dx.doi.org/10.1016/j.jns.2017.05.047

  18. Najjar RP, Sharma S, Drouet M, Leruez S, Baskaran M, Nongpiur ME, Aung Tin, Fielding J, White O, Lamirel C, Milea D. Disrupted Eye Movements in Preperimetric Glaucoma. Invest Ophthalmol Vis Sci, 2017 Apr 1;58(4):2430-2437. https://dx.doi.org/10.1167/iovs.16-21002

  19. Lo YL, Najjar RP, Teo KY, Tow S, Loo JL, Milea D. A reappraisal of diagnostic tests for myasthenia gravis in a large Asian cohort. J Neurol Sci, 2017, May 15;376:153-158. https://dx.doi.org/10.1016/j.jns.2017.03.016

  20. Wang X, Milea D, Girard M. Predictions of Optic Nerve Traction Forces and Peripapillary Tissue Stresses Following Horizontal Eye Movements. Invest Ophthalmol Vis Sci, 2017, Apr ;58(4) :2044-2053. https://dx.doi.org/10.1167/iovs.16-21319

  21. Loo JL, SInghal S, Tow S, Amati-Bonneau P, Procaccio V, Bonneau D, Reynier P, Ferre M, Milea D. Multiethnic involvement in autosomal dominant optic atrophy in Singapore. Eye (London), 2017 Mar;31(3):475-480. https://dx.doi.org/10.1038/eye.2016.255

  22. Rukmini AV, Milea D, Aung T, Gooley J. Pupillary responses to short-wavelength light are preserved in aging. Sci Rep. 2017 Mar 7;7:43832. https://dx.doi.org/10.1038/srep43832

  23. Yong Z, Hsieh PJ, Milea D. Seeing the sound after visual loss : functional MRI in acquired auditory-visual synesthesia. Exp Brain Res, 2017 Feb;235(2):415-420. https://dx.doi.org/10.1007/s00221-016-4802-6

  24. Hung SM, Milea D, Viénot F, Rukmini DV, Najjar RP, Tan JH, Dubail, M, Tow SLC, Aung T, Gooley JJ, Hsieh PJ. Neural correlates of melanopic-mediated retinal photoreception. NeuroImage, 2017 Feb 1;146:763-769. https://dx.doi.org/10.1016/j.neuroimage.2016.09.061

  25. Chao de la Barca JM, Simard G, Sarzi E, Chaumette T, Rousseau G, Chupin S, Gadras C, Tessier L, Ferré M, Chevrollier A, Desquiret-Dumas V, Gueguen N, Leruez S, Verny C, Miléa D, Bonneau D, Amati-Bonneau P, Procaccio V, Hamel C, Lenaers G, Reynier P, Prunier-Mirebeau D. Targeted metabolomics reveals early dominant atrophy signature in optic nerves of Opa1delTTAG+/-  mice. Invest Ophthalmol Vis Sci. 2017 Feb 1;58(2):812-820. https://dx.doi.org/10.1167/iovs.16-21116

  26. Najjar RP, Milea D. Can Photoreceptor Loss Also Account for Changes in Pupil Size Following Panretinal Photocoagulation? Eye (London), 2017, 235(2) :415-420. https://dx.doi.org/10.1038/eye.2016.210

  27. Sidibé D, Sankar S, Lemaître G, Rastgoo M, Massich J, Cheung CY, Tan GS, Milea D, Lamoureux E, Wong TY, Mériaudeau F. An anomaly detection approach for the identification of DME patients using spectral domain optical coherence tomography images. Comput Methods Programs Biomed. 2017 Feb;139:109-117. https://dx.doi.org/10.1016/j.cmpb.2016.11.001

  28. Chao de la Barca J, Simard G, Amati Bonneau P, Safiedeen Z, Prunier-Mirebeau D, Chupin S, Gadras G, Tessier L, Gueguen N, Chevrollier A, Desquiret-Dumas A, Ferré M, Bris C, Nzoughet JK, Bocca C, Leruez S, Verny C, Miléa D, Bonneau D, Lenaers G, Martinez MC, Procaccio V, Reynier P. The metabolomic signature of Leber’s hereditary optic neuropathy reveals endoplasmic reticulum stress. Brain, 2017. https://doi.org/10.1093/brain/aww222


Members

Prof Dan Milea, PhD
Head, Visual Neuroscience Group, SERI
Senior Clinician, Neuro-Ophthalmology, SNEC
Professor, Duke-NUS Medical School
dan.milea@snec.com.sg


Dr Raymond P. Najjar, PhD

Neuroscientist
Senior Research Fellow, SERI
Instructor, Duke-NUS Medical School
raymond.najjar@seri.com.sg


Dr Chougule Pratik Sukhdev, DNB

Neuro-ophthalmologist
Clinical Research Fellow, SERI
chougule.pratik.sukhdev@seri.com.sg


Dr Petteri Teikari Joni, PhD

Biomedical Engineer, Neuroscientist
Research Fellow, SERI
teikari.petteri.joni@seri.com.sg


Dr AR Muralidharan, PhD

Molecular Biologist
Research Fellow, SERI
a.r.muralidharan@seri.com.sg