The Visual Neuroscience 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 behavioural and physiological consequences of diseases affecting the retina and/or 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. Artificial Intelligence in Neuro-Ophthalmology and Visual Neurosciences
Our group has developed an international consortium, BONSAI (Brain and Optic Nerve Study with Artificial Intelligence), with the aim to detect brain and optic nerves abnormalities using an artificial intelligence-based analysis of standard retinal photographs. We have so far obtained major outcomes in this field, recently published in prestigious international medical journals, such as The New England Journal of Medicine, as well as other major journals in Neurology, concerning detection/performance/severity classification of papilledema and other optic neuropathies by our deep learning system. We foresee new applications and developments of this research area in our lab, in the near future.
2. 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 simple to use, portable chromatic pupillometry, devices correlate 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).
3. The Neurobiology of Photic Interventions for Myopia-Control
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 is protective 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 an effort spearheaded by Dr Raymond Najjar, our group aims to understand the neurobiology behind light-driven myopia-control and develop tailored light therapy strategies for the prevention of myopia.
We have recently developed a state-of-the-art research facility for evaluating the impact of light (intensity, spectrum, timing and duration) on different animal models including non-human primate (NHP). The NHP model includes Rhesus and Cynomolgus Macaques and was successfully developed in collaboration with Professor Earl Smith and Dr Li-Fang Hung (University of Houston, USA) using custom-built 3D-printed helmets equipped unilaterally with a Bangerter occlusion foil. We are currently using this model to evaluate the chronic impact of intermittent high intensity light exposures on ocular growth, myopia development and ocular vasculature and structure using swept-source optical coherence tomography-angiography (SS-OCT A) (Plex Elite 9000, Zeiss). Intermittent exposure to high intensity light is showing promising results in preventing the onset of myopia in NHPs. Dr Najjar’s team is also investigating 1/ the synergetic impact of defocus interruption and high intensity light (Biswas et al. 2021 — ARVO) and 2/ the impact of spectrally tailored indoor lighting strategies (Najjar et al. 2021, Sci Rep., Muralidharan et al. 2020 — ARVO) on emmetropization and ocular growth and metabolomics in chicken models of form-deprivation and lens-induced myopia. The ultimate goal of the group is to translate findings in the NHP and chicken models into feasible light therapy strategies for myopia prevention.
These projects are in collaboration with the Myopia (Co-Heads: Professor Saw Seang Mei, Associate Professor Audrey Chia) and Ocular Imaging (Head: Professor Leopold Schmetterer) SERI Research Groups and with the support of the Translational Preclinical Model Platform at SERI led by Dr Veluchamy Amutha Barathi, in addition to international collaborators (Biochemistry and Genetics Lab, CHU Angers, France).
Recent findings:
We have recently reported that the spectral composition of white light can affect ocular growth and metabolomics. In a work published in Scientific Reports (Najjar et al. 2021) we evaluated the impact of moderate levels of ambient standard white (SW: 233.1 lux, 3900 K) and blue-enriched white (BEW: 223.8 lux, 9700 K) lights on ocular growth and metabolomics in a chicken-model of form-deprivation myopia. Compared to SW light, BEW light decreased aberrant ocular axial elongation and accelerated recovery from form-deprivation. Furthermore, the metabolomic profiles in the vitreous and retinas of recovering form-deprived eyes were distinct from control eyes and were dependent on the spectral content of ambient light. For instance, exposure to BEW light was associated with deep lipid remodelling and metabolic changes related to energy production, cell proliferation, collagen turnover and nitric oxide metabolism. This study provides new insight on light-dependent modulations in ocular growth and metabolomics. If replicable in humans, our findings open new potential avenues for spectrally tailored light-therapy strategies for myopia.
Our team has also evaluated the impact of full-spectrum light-emitting diodes (LEDs) mimicking sunlight on ocular axial elongation and refractive error development in a chicken model of myopia and it was noted that compared to fluorescent lights moderate intensity (~285 lux) of Sunlike LEDs are capable of accelerating the recovery from form-deprivation myopia (Muralidharan et al., ARVO 2020 e-abstract). These studies also highlight an important role of the spectral content of white light in modulating emmetropization and ocular growth. Furthermore, our group is also involved in understanding the synergistic effect of bright light (~15,000 lux), and optical refocus on myopia development using a chicken model of lens-induced myopia (Sayantan et al., ARVO 2021).
4. 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.
5. 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 behavioural 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 behavioural biomarkers of neurodegenerative conditions, like AD and PD.
Chan E, Najjar RP, Tang Z, Milea D. Artificial intelligence for retinal image quality assessment of optic nerve head disorders. Asia-Pacific Journal of Ophthalmology. 2021, in press.
Ng WY, Cheung CY, Milea D, Ting DSW. Artificial intelligence and machine learning for Alzheimer’s disease: Let’s not forget about the retina. Br J Ophthalmol. 2021 May;105(5):593-594. doi: 10.1136/bjophthalmol-2020-318407.
Biousse V, Newman NJ, Najjar RP, Vasseneix C, Xu X, Ting DS, Milea LB, Hwang JM, Kim DH, Yang HK, Hamann S, Chen JJ, Liu Y, Wong TY, Milea D, BONSAI (Brain and Optic Nerve Study with Artificial Intelligence) Study Group. Optic disc classification by deep learning versus expert neuro-ophthalmologists. Ann Neurol. 2020 Oct;88(4):785-795.
Milea D, Najjar RP, Zhubo J, Ting D, Vasseneix C, Xu X, Aghsaei Fard M, Fonseca P, Vanikieti K, Lagrèze Wa, La Morgia C, Cheung CY, Hamann S, Chiquet C, Sanda N, Yang H, Mejico LJ, Rougier M-B, Kho R, thi ha Chau T, Singhal S, Gohier P, Clermont-Vignal C, Cheng C-Y, Jonas JB, Yu-Wai-Man P, Fraser CL, Chen JJ, Ambika S, Miller NR, Liu Y, Newman NJ, Wong TY, Biousse V, BONSAI (Brain and Optic Nerve Study with Artificial Intelligence) Study Group. Artificial intelligence to detect papilledema from ocular fundus photographs. N Engl J Med. 2020;382(18):1687-1695.
Milea D, Singhal S, Najjar RP. Artificial intelligence for detection of optic disc abnormalities. Curr Opin Neurol. 2020 Feb;33(1):106-110.
Vasseneix C, Najjar RP, Xu X, Tang Z, Loo JL, Singhal S, Tow S, Milea L, Ting DSW, Liu Y, Wong TY, Newman NJ, Biousse V, Milea D, BONSAI Group. Accuracy of a deep learning system for classification of papilledema severity on ocular fundus photographs. Neurology. 2021 May 19:10.1212/WNL.0000000000012226. doi: 10.1212/WNL.0000000000012226. Online ahead of print.
Najjar RP, Chao De La Barca JM, Barathi VA, Ho Ceh, Lock JZ, Muralidharan AR, Tan RKY, Dhand C, Lakshminarayanan R, Reynier P, Milea D. Ocular growth and metabolomics are dependent upon the spectral content of ambient white light. Sci Rep. 2021 Apr 7;11(1):7586. doi:10.1038/s41598-021-87201.
Najjar RP, Reynier P, Caignard A, Procaccio V, Amati-Bonneau P, Mack H, Milea D. Retinal neuronal loss in visually asymptomatic patients with myoclonic epilepsy with ragged-red fibers. J Neuroophthalmol. 2019 Mar;39(1):18-22. doi: 10.1097/WNO.0000000000000690.
Faroqui S, Chan A, Cullen B, Milea D. Too young to undergo temporal artery biopsy? Calciphylaxis-related anterior ischemic optic neuropathy. Neuro-Ophthalmology. 2019 Aug;43(4):252-255. doi: 10.1080/01658107.2018.1493739.
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.
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):699707. https://dx.doi.org/10.1007/s00417-018-3937-5.
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. doi: 10.1186/s41606-018-0022-2. https://doi.org/10.1186/s41606-018-0022-2.
Najjar RP, Sharma S, Atalay E, Rukmini AV, Sun C, Lock JZ, Baskaran M, Perera S, Hussain R, Lamoureux E, Gooley JJ, Aung T, Milea D. Pupillary responses to full-field chromatic stimuli are reduced in patients with early-stage primary open-angle glaucoma. Ophthalmology. 2018 Sep;125(9):1362-1371. doi: 10.1016/j.ophtha.2018.02.024. https://doi.org/10.1016/j.ophtha.2018.02.024.
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, acylcarnitines and polyamines. Invest Ophthalmol Vis Sci. 2018 Feb 1;59(2):1025-1032.
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 J Rare Dis. 2018 Feb 17;13(1):33. https://dx.doi.org/10.1186/s13023-018-0773-y.
Najjar RP, Zeitzer JM. Chapter 2 – 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.
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.
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.
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 (Lond). 2018 Feb;32(2):262-286. https://dx.doi.org/ 10.1038/eye.2017.181.
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. doi: 10.1002/mus.25983. Epub 2017 Nov 2. https://dx.doi.org/ 10.1002/mus.25983.
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.
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.
Aung T, Ozaki M, …Milea D, …., Pasutto F, Khor CC. Genetics association study of exfoliation syndrome identifies a protective rare variant at LOXL1 and five new susceptibility loci. Nat Genet. 2017 Jul;49(7):993-1004. https://dx.doi.org/ 10.1038/ng.3875.
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.
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.
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.
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.
Loo JL*, Singhal S*, Rukmini AV, Tow S, Amati-Bonneau P, Procaccio V, Bonneau D, Gooley JJ, Reynier P, Ferré M, Milea D. Multiethnic involvement in autosomal-dominant optic atrophy in Singapore. Eye (Lond). 2017 Mar;31(3):475-480. https://dx.doi.org/10.1038/eye.2016.255.
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.
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.
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.
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.
Najjar RP, Milea D. Can photoreceptor loss also account for changes in pupil size following panretinal photocoagulation? Eye (Lond). 2017 Jan;31(1):161. Correspondence. https://dx.doi.org/10.1038/eye.2016.210.
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.
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. 2016 Nov 1;139(11):2864-2876. https://doi.org/10.1093/brain/aww222.
Prof Dan Milea, PhDHead, Visual Neuroscience Research Group, SERISenior Clinician, Neuro-Ophthalmology, SNECProfessor, Duke-NUS Medical School
Dr Raymond P. Najjar, PhDNeuroscientistJunior Principal Investigator, SERIAssistant Professor, Duke-NUS Medical School
Dr AR Muralidharan, PhDMolecular BiologistResearch Fellow, SERI
Dr Sayantan Biswas, PhDVision ScientistResearch Fellow, SERI
Dr Tang Zhiqun, PhDData ScientistSenior Research Fellow II, Visual Neuroscience Research Group, SERI
Mr Vayne Lee Yong Chong, DVMVeterinarianResearch Officer, SERI
Ms Janie Tay Hwee ChingAssociate Research Coordinator, SERI
Ms Liu ChenjingClinical Research Coordinator, SERI
Ms Megan Tay Mei ChenOphthalmic Research Technician, SERI
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