Optometry and Vision Sciences - Research Publications

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    Implantation and Recording of Wireless Electroretinogram and Visual Evoked Potential in Conscious Rats
    Charng, J ; He, Z ; Bui, B ; Vingrys, A ; Ivarsson, M ; Fish, R ; Gurrell, R ; Nguyen, C (JOURNAL OF VISUALIZED EXPERIMENTS, 2016-06-01)
    The full-field electroretinogram (ERG) and visual evoked potential (VEP) are useful tools to assess retinal and visual pathway integrity in both laboratory and clinical settings. Currently, preclinical ERG and VEP measurements are performed with anesthesia to ensure stable electrode placements. However, the very presence of anesthesia has been shown to contaminate normal physiological responses. To overcome these anesthesia confounds, we develop a novel platform to assay ERG and VEP in conscious rats. Electrodes are surgically implanted sub-conjunctivally on the eye to assay the ERG and epidurally over the visual cortex to measure the VEP. A range of amplitude and sensitivity/timing parameters are assayed for both the ERG and VEP at increasing luminous energies. The ERG and VEP signals are shown to be stable and repeatable for at least 4 weeks post surgical implantation. This ability to record ERG and VEP signals without anesthesia confounds in the preclinical setting should provide superior translation to clinical data.
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    Reversibility of retinal ganglion cell dysfunction due to chronic IOP elevation.
    Zhao, D ; Wong, VHY ; He, Z ; Nguyen, CTO ; Jobling, AI ; Fletcher, E ; Chinnery, H ; Jusuf, P ; Lim, JKH ; Vingrys, AJ ; Bui, BV (Association for Research in Vision and Ophthalmology, 2018-07-01)
    Purpose : To determine the duration of chronic IOP elevation beyond which ganglion cell function can no longer recover using the mouse circumlimbal suture model. Methods : IOP elevation was induced in anaesthetized (isoflurane) adult male C57BL6/J mice by attaching a circumlimbal suture (nylon, 10/0) around the equator of one eye, with the contralateral eye serving as a control. The suture was left in place for 8, 12 and 16 weeks (n=27, 23 and 27), respectively, and animals underwent electroretinography and optical coherence tomography at these time points. In two other groups, the suture was removed after 8 and 12 weeks (n=26 and 28), and the capacity for recovery assessed 4 weeks later. IOP was measured weekly (Tonolab). Retinal ganglion cell (RGC) function (or integrity) was assessed with the positive scotopic threshold response (pSTR) and retinal nerve fibre layer (RNFL) thickness. Data (mean ± SEM) were compared using t-test (control vs. treatment) and one-way ANOVA (within groups). Results : IOP in sutured eyes was higher than control eyes (8wk: 17.1 ± 0.3 vs. 26.8 ± 0.6 mmHg, 12wk: 13.8 ± 0.3 vs. 19.5 ± 0.5 mmHg, 16wk: 17.1 ± 0.2 vs. 27.4 ± 0.6 mmHg; all P<0.001). After suture removal, IOP returned to levels comparable to control eyes (8+4wk: 16.9 ± 0.3 vs. 16.1 ± 0.3 mmHg; P=0.08, 12+4wk: 17.3 ± 0.2 vs. 17.1 ± 0.3 mmHg; P=0.5). With IOP elevation, RGC function declined to 75% ± 8% (8wk), 78% ± 7% (12wk) and 59% ± 4% (16wk, all P<0.001) of control eyes. RNFL thinning was also evident (8wk: 84% ± 4%, 12wk: 83% ± 5%; 16wk: 83% ± 3%; P<0.001) but no change in total retinal thickness was noted (P=0.33). Suture removal at week 8 facilitated full recovery of RGC function (97% ± 7%, P=0.9 vs. baseline) 4 weeks later. However, there was no recovery in RNFL thickness (87% ± 3%, P<0.001 vs. baseline). When the suture was removed at week 12, neither function (79% ± 9%, P<0.05) nor RNFL thickness recovered (89% ± 3%, P<0.01) 4 weeks later. Conclusions : RGC dysfunction can be recovered 4 weeks after an 8-week period of mild IOP elevation, but not after a 12-week period. Beyond 12 weeks, IOP reversal only served to prevent further functional decline. This identifies a critical chronic IOP duration that results in irreversible ganglion cell dysfunction. This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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    Response of the Rat Optic Nerve to Acute Intraocular and Intracranial Pressure Changes
    Zhao, D ; He, Z ; Van Koeverden, A ; Vingrys, AJ ; Wong, VHY ; Lim, JKH ; Nguyen, CTO ; Bui, BV ; Wang, N (Springer, 2019)
    Glaucoma is a neurodegenerative disease, characterized by the progressive death of retinal ganglion cells. Elevated intraocular pressure (IOP) is known to be an important risk factor for glaucoma; however, it is not the only force acting on the optic nerve. Intracranial pressure (ICP) also exerts an effect on the optic nerve head, effectively opposing the force applied by IOP. Indeed, this balance of forces creates a pressure gradient (or the translaminar pressure gradient) across the optic nerve head [1]. Increasingly it is thought that the pressure difference between IOP and ICP, the translaminar pressure (TLP), may be critical for the integrity of the retina and optic nerve [2], and thus ICP may be an important risk factor for glaucoma [2–6].
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    A Model of Glaucoma Induced by Circumlimbal Suture in Rats and Mice
    He, Z ; Zhao, D ; van Koeverden, AK ; Nguyen, CT ; Lim, JKH ; Wong, VHY ; Vingrys, AJ ; Bui, BV (Journal of Visualized Experiments, 2018)
    The circumlimbal suture is a technique for inducing experimental glaucoma in rodents by chronically elevating intraocular pressure (IOP), a well-known risk factor for glaucoma. This protocol demonstrates a step-by-step guide on this technique in Long Evans rats and C57BL/6 mice. Under general anesthesia, a "purse-string" suture is applied on the conjunctiva, around the equator and behind the limbus of the eye. The fellow eye serves as an untreated control. Over the duration of our study, which was a period of 8 weeks for rats and 12 weeks for mice, IOP remained elevated, as measured regularly by rebound tonometry in conscious animals without topical anesthesia. In both species, the sutured eyes showed electroretinogram features consistent with preferential inner retinal dysfunction. Optical coherence tomography showed selective thinning of the retinal nerve fiber layer. Histology of the rat retina in cross-section found reduced cell density in the ganglion cell layer, but no change in other cellular layers. Staining of flat-mounted mouse retinae with a ganglion cell specific marker (RBPMS) confirmed ganglion cell loss. The circumlimbal suture is a simple, minimally invasive and cost-effective way to induce ocular hypertension that leads to ganglion cell injury in both rats and mice.
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    How ganglion cell responses to IOP elevation are impacted by blood pressure and intracranial pressure
    Bui, BV ; van Koeverden, A ; He, Z ; Vingrys, AJ ; Nguyen, CTO ; Zhao, D (Association for Research in Vision and Ophthalmology, 2019-07-01)
    Purpose : The extent to which blood pressure or intracranial pressure modifies ganglion cell responses to acute intraocular pressure (IOP) elevation incompletely understood. Using the electroretinogram (ERG) we measure ganglion cell mediated responses in rat retina, whilst acutely modifying IOP, BP and ICP in a systematic manner. We quantify the relationship between ganglion cell function and ocular perfusion pressure (BP - IOP) at low, normal and high ICP. Methods : Six groups of adult Long-Evans rats (n=7-11 eyes/group, total animals = 25) were anaesthetised (60:5mg/kg ketamine:xylazine) and underwent acute pressure modification. A femoral artery and vein were cannulated for blood pressure measurement and manipulation (sodium nitroprusside to lower and angiotensin II to elevate pressure). ICP was set to -5, 5 or 25 mmHg via a dual cannula (30G infusion needle inside a 23G measurement needle) placed into the lateral ventricle (-1.5mm from bregma, ±2mm from midline) on the ipsilateral side to the cannulated eye (30G, vitreal chamber). At each ICP (-5, 5 or 25 mmHg) and BP setting (normal or high), IOP was raised from 10 to 90 mmHg in 10 mmHg steps (3 min each). At each IOP level ganglion cell function was assessed using the scotopic threshold response (-5 log cd.s/m2, 20 repeats). Data were compared using one- and two-way ANOVA. Results : Average blood pressure at baseline was similar for the normal blood pressure groups (ICP-5 93±3; ICP5 99±5; ICP25 105±3mmHg, p=0.8). There was significant BP elevation in all the high blood pressure groups (ICP-5 160±3; ICP5 157±3; ICP25 157±5mmHg p<0.001). Compared with normal blood pressure groups (32.0±2.0μV), animals with high blood pressure (24.5±1.8μV) had significantly smaller baseline STR amplitudes (p<0.01). There was also a significant ICP effect (p<0.01), with larger baseline amplitudes in the 25mmHg ICP group (34.8±1.6μV) compared with normal (26.4±2.5μV) and low ICP groups (23.9±2.5μV). The ocular perfusion pressure (BP-IOP) relationship fully could not account for difference in ganglion cell function between ICP levels. Conclusions : Ganglion cell function is dependent on ocular perfusion pressure, excessive low or high perfusion attenuates function. Higher intracranial pressure appears to protect against acute ocular perfusion stress.
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    Reversal of functional loss in a rat model of chronic intraocular pressure elevation
    Liu, H-H ; He, Z ; Nguyen, CTO ; Vingrys, AJ ; Bui, BV (WILEY, 2017-01-01)
    PURPOSE: This pilot study considered whether intraocular pressure (IOP) lowering could reverse ganglion cell dysfunction in a rat model of chronic ocular hypertension. METHODS: A circumlimbal suture was applied in one eye to induce ocular hypertension (n = 7) in Long-Evans rats. The contralateral eye served as an untreated control. After 8 weeks of IOP elevation the suture was removed to lower IOP for the remaining 7 weeks. Electroretinogram (ERG) and optical coherence tomography (OCT) were measured at baseline, 2, 4, 8, 12 and 15 weeks. Retinae were collected for histology at week 15. RESULTS: In sutured eyes, IOP was elevated by 7-11 mmHg above control eyes (12 ± 0.2 mmHg [standard error of the mean]). Eight weeks of chronic IOP elevation resulted in a reduction of the ganglion cell mediated positive Scotopic Threshold Response (pSTR, -25 ± 7% of baseline), as well as smaller photoreceptor (-7 ± 4%) and bipolar cell mediated responses (-6 ± 5%). After suture removal, IOP recovered to normal. By 15 weeks the a-wave (0 ± 6%), b-wave (-2 ± 6%) and pSTR had recovered back to baseline (from -25 ± 7% to -4 ± 6%). The retinal nerve fiber layer was thinned by -9 ± 3% at week 8 and showed no further decline at week 15 (-10 ± 2%). Cell numbers in the ganglion cell layer were similar between suture removal and control eyes at week 15 (3543 ± 478 vs 4057 ± 476 cells mm-2 ). CONCLUSIONS: The circumlimbal suture model might be a useful platform to study the reversibility of neuronal dysfunction from chronic IOP challenge.
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    Retinal Functional and Structural Changes in the 5xFAD Mouse Model of Alzheimer's Disease
    Lim, JKH ; Li, Q-X ; He, Z ; Vingrys, AJ ; Chinnery, HR ; Mullen, J ; Bui, BV ; Nguyen, CTO (FRONTIERS MEDIA SA, 2020-08-13)
    Alzheimer's disease is characterized by the aberrant deposition of protein in the brain and is the leading cause of dementia worldwide. Increasingly, there have been reports of the presence of these protein hallmarks in the retina. In this study, we assayed the retina of 5xFAD mice, a transgenic model of amyloid deposition known to exhibit dementia-like symptoms with age. Using OCT, we found that the retinal nerve fiber layer was thinner in 5xFAD at 6, 12, and 17 months of age compared with wild-type littermates, but the inner plexiform layer was thicker at 6 months old. Retinal function showed reduced ganglion cell responses to light in 5xFAD at 6, 12, and 17 months of age. This functional loss was observed in the outer retina at 17 months of age but not in younger mice. We showed using immunohistochemistry and ELISA that soluble and insoluble amyloid was present in the retina and brain at all ages. In conclusion, we report that amyloid is present in brain and retina of 5xFAD mice and that the pattern of neuronal dysfunction occurs in the inner retina at the early ages and progresses to encompass the outer retina with age. This implies that the inner retina is more sensitive to amyloid changes in early disease and that the outer retina is also affected with disease progression.
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    Conscious Wireless Electroretinogram and Visual Evoked Potentials in Rats
    Charng, J ; Nguyen, CT ; He, Z ; Dang, TM ; Vingrys, AJ ; Fish, RL ; Gurrell, R ; Brain, P ; Bui, BV ; Frishman, L (PUBLIC LIBRARY SCIENCE, 2013-09-12)
    The electroretinogram (ERG, retina) and visual evoked potential (VEP, brain) are widely used in vivo tools assaying the integrity of the visual pathway. Current recordings in preclinical models are conducted under anesthesia, which alters neural physiology and contaminates responses. We describe a conscious wireless ERG and VEP recording platform in rats. Using a novel surgical technique to chronically implant electrodes subconjunctivally on the eye and epidurally over the visual cortex, we are able to record stable and repeatable conscious ERG and VEP signals over at least 1 month. We show that the use of anaesthetics, necessary for conventional ERG and VEP measurements, alters electrophysiology recordings. Conscious visual electrophysiology improves the viability of longitudinal studies by eliminating complications associated with repeated anaesthesia. It will also enable uncontaminated assessment of drug effects, allowing the eye to be used as an effective biomarker of the central nervous system.
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    Systemic hypertension is not protective against chronic intraocular pressure elevation in a rodent model
    van Koeverden, AK ; He, Z ; Nguyen, CTO ; Vingrys, AJ ; Bui, BV (NATURE PUBLISHING GROUP, 2018-05-08)
    High intraocular pressure is the most well documented glaucoma risk factor; however many patients develop and/or show progression of glaucoma in its absence. It is now thought that in some instances, ocular perfusion pressure (blood pressure - intraocular pressure) may be as important as intraocular pressure alone. Thus, systemic hypertension would be protective against glaucoma. Epidemiological studies, however, are inconclusive. One theory of why hypertension may not protect against elevated intraocular pressure in spite of increasing ocular perfusion pressure is that with time, morphological changes to the vasculature and autoregulatory failure outweigh the benefits of improved perfusion pressure, ultimately leading to poor retinal and optic nerve head blood supply. In this study we showed the presence of increased wall:lumen ratio and wall area of the ophthalmic artery in rats with chronic hypertension in addition to failure of retinal autoregulation in response to acute modification of ocular perfusion pressure. Subsequently we found that in spite of dramatically increasing ocular perfusion pressure, chronic systemic hypertension failed to protect retinal structure and function from a rodent model of glaucoma.
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    Age-related changes in the response of retinal structure, function and blood flow to pressure modification in rats
    Zhao, D ; Nguyen, CTO ; He, Z ; Wong, VHY ; van Koeverden, AK ; Vingrys, AJ ; Bui, BV (NATURE PUBLISHING GROUP, 2018-02-13)
    Age-related changes to the balance between the pressure inside the eye (intraocular pressure, IOP) and the pressure inside the brain (intracranial pressure, ICP) can modify the risk of glaucoma. In this study, we consider whether the optic nerve in older rat eyes is more susceptible to acute IOP and ICP modification. We systematically manipulate both ICP and IOP and quantify their effects on ganglion cell function (electroretinography, ERG), optic nerve structure (optical coherence tomography, OCT) and retinal blood flow (Doppler OCT). We show that ganglion cell function in older eyes was more susceptible to a higher optic nerve pressure difference (ONPD = IOP - ICP). This age-related susceptibility could not be explained by poorer blood flow with elevated ONPD. Rather, as ONPD increased the retinal nerve fibre layer showed greater compression, and the retinal surface showed less deformation in older eyes. Our data suggest that age-related changes to connective tissues in and around the rat optic nerve make it less flexible, which may result in greater strain on ganglion cell axons. This may account for greater functional susceptibility to higher optic nerve pressure differences in older rat eyes. Further studies in a species with a well-developed lamina cribrosa are needed to determine the clinical importance of these observations.