Optometry and Vision Sciences - Research Publications
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ItemConscious Wireless Electroretinogram and Visual Evoked Potentials in Rats(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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ItemNo Preview AvailableChronic Hypertension Increases Susceptibility to Acute IOP Challenge in Rats(ASSOC RESEARCH VISION OPHTHALMOLOGY INC, 2014-12)PURPOSE: To consider the effect of chronic arterial hypertension on the susceptibility of the retina to acute IOP challenge. METHODS: Anesthetized adult Long-Evans rats with normal (n = 5, receiving saline subcutaneously), chronic high blood pressure (BP) for 4 weeks (n = 15, Angiotensin II subcutaneously), and acute high BP for 1 hour (n = 10, Angiotensin II intravenously) underwent IOP elevation (10-120 mm Hg, 5 mm Hg steps each 3 minutes). During IOP elevation, retinal function and ocular blood flow were monitored with electroretinogram (ERG) and laser-Doppler flowmetry (LDF), respectively. Blood pressure was monitored via a femoral artery cannula. Electroretinogram and LDF responses are expressed as a percentage of baseline and compared between groups. The left ventricle and the aorta were dissected to assess the morphologic changes associated with chronic hypertension. RESULTS: Four weeks of hypertension (systolic BP 192 ± 4 mm Hg) produced cardiac hypertrophy and thickened aortic arterial walls compared with controls (systolic BP 112 ± 3 mm Hg). Retinal function was unaltered with chronic hypertension compared with normotensive animals. During acute IOP elevation, ERG and LDF were reduced in a dose-dependent manner in all BP groups. Both chronic and acute hypertension made the ERG and LDF less susceptible to IOP elevation. However, the degree of resistance to IOP elevation was greater in acute hypertension compared with chronic hypertension (P < 0.05). CONCLUSIONS: Acute BP elevation makes retinal function and blood flow less susceptible to IOP elevation. The reduced susceptibility afforded by improved ocular perfusion pressure is compromised after 4 weeks of chronic hypertension.
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ItemCoupling blood flow and neural function in the retina: a model for homeostatic responses to ocular perfusion pressure challenge(WILEY, 2013-08)Retinal function is known to be more resistant than blood flow to acute reduction of ocular perfusion pressure (OPP). To understand the mechanisms underlying the disconnect between blood flow and neural function, a mathematical model is developed in this study, which proposes that increased oxygen extraction ratio compensates for relative ischemia to sustain retinal function. In addition, the model incorporates a term to account for a pressure-related mechanical stress on neurons when OPP reduction is achieved by intraocular pressure (IOP) elevation. We show that this model, combining ocular blood flow, oxygen extraction ratio, and IOP mechanical stress on neurons, accounts for retinal function over a wide range of OPP manipulations. The robustness of the model is tested against experimental data where ocular blood flow, oxygen tension, and retinal function were simultaneously measured during acute OPP manipulation. The model provides a basis for understanding the retinal hemodynamic responses to short-term OPP challenge.
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ItemIdentifying Cell Class Specific Losses from Serially Generated Electroretinogram Components(HINDAWI LTD, 2013)PURPOSE: Processing of information through the cellular layers of the retina occurs in a serial manner. In the electroretinogram (ERG), this complicates interpretation of inner retinal changes as dysfunction may arise from "upstream" neurons or may indicate a direct loss to that neural generator. We propose an approach that addresses this issue by defining ERG gain relationships. METHODS: Regression analyses between two serial ERG parameters in a control cohort of rats are used to define gain relationships. These gains are then applied to two models of retinal disease. RESULTS: The PIII(amp) to PII(amp) gain is unity whereas the PII(amp) to pSTR(amp) and PII(amp) to nSTR(amp) gains are greater than unity, indicating "amplification" (P < 0.05). Timing relationships show amplification between PIII(it) to PII(it) and compression for PII(it) to pSTR(it) and PII(it) to nSTR(it), (P < 0.05). Application of these gains to ω-3-deficiency indicates that all timing changes are downstream of photoreceptor changes, but a direct pSTR amplitude loss occurs (P < 0.05). Application to diabetes indicates widespread inner retinal dysfunction which cannot be attributed to outer retinal changes (P < 0.05). CONCLUSIONS: This simple approach aids in the interpretation of inner retinal ERG changes by taking into account gain characteristics found between successive ERG components of normal animals.
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ItemQuantitative Spatial and Temporal Analysis of Fluorescein Angiography Dynamics in the Eye(PUBLIC LIBRARY SCIENCE, 2014-11-03)PURPOSE: We describe a novel approach to analyze fluorescein angiography to investigate fluorescein flow dynamics in the rat posterior retina as well as identify abnormal areas following laser photocoagulation. METHODS: Experiments were undertaken in adult Long Evans rats. Using a rodent retinal camera, videos were acquired at 30 frames per second for 30 seconds following intravenous introduction of sodium fluorescein in a group of control animals (n = 14). Videos were image registered and analyzed using principle components analysis across all pixels in the field. This returns fluorescence intensity profiles from which, the half-rise (time to 50% brightness), half-fall (time for 50% decay) back to an offset (plateau level of fluorescence). We applied this analysis to video fluorescein angiography data collected 30 minutes following laser photocoagulation in a separate group of rats (n = 7). RESULTS: Pixel-by-pixel analysis of video angiography clearly delineates differences in the temporal profiles of arteries, veins and capillaries in the posterior retina. We find no difference in half-rise, half-fall or offset amongst the four quadrants (inferior, nasal, superior, temporal). We also found little difference with eccentricity. By expressing the parameters at each pixel as a function of the number of standard deviation from the average of the entire field, we could clearly identify the spatial extent of the laser injury. CONCLUSIONS: This simple registration and analysis provides a way to monitor the size of vascular injury, to highlight areas of subtle vascular leakage and to quantify vascular dynamics not possible using current fluorescein angiography approaches. This can be applied in both laboratory and clinical settings for in vivo dynamic fluorescent imaging of vasculature.
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ItemBlood Pressure Modifies Retinal Susceptibility to Intraocular Pressure Elevation(PUBLIC LIBRARY SCIENCE, 2012-02-16)Primary open angle glaucoma affects more than 67 million people. Elevated intraocular pressure (IOP) is a risk factor for glaucoma and may reduce nutrient availability by decreasing ocular perfusion pressure (OPP). An interaction between arterial blood pressure and IOP determines OPP; but the exact contribution that these factors have for retinal function is not fully understood. Here we sought to determine how acute modifications of arterial pressure will affect the susceptibility of neuronal function and blood flow to IOP challenge. Anaesthetized (ketamine:xylazine) Long-Evan rats with low (∼60 mmHg, sodium nitroprusside infusion), moderate (∼100 mmHg, saline), or high levels (∼160 mmHg, angiotensin II) of mean arterial pressure (MAP, n = 5-10 per group) were subjected to IOP challenge (10-120 mmHg, 5 mmHg steps every 3 minutes). Electroretinograms were measured at each IOP step to assess bipolar cell (b-wave) and inner retinal function (scotopic threshold response or STR). Ocular blood flow was measured using laser-Doppler flowmetry in groups with similar MAP level and the same IOP challenge protocol. Both b-wave and STR amplitudes decreased with IOP elevation. Retinal function was less susceptible to IOP challenge when MAP was high, whereas the converse was true for low MAP. Consistent with the effects on retinal function, higher IOP was needed to attenuated ocular blood flow in animals with higher MAP. The susceptibility of retinal function to IOP challenge can be ameliorated by acute high BP, and exacerbated by low BP. This is partially mediated by modifications in ocular blood flow.
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ItemThe Effect of Ageing on Ocular Blood Flow, Oxygen Tension and Retinal Function during and after Intraocular Pressure Elevation(PUBLIC LIBRARY SCIENCE, 2014-05-27)PURPOSE: To investigate the effect of ageing on the recovery of ocular blood flow, intravitreal oxygen tension and retinal function during and after intraocular pressure (IOP) elevation. METHODS: Long Evans rats (3- and 14-month-old) underwent acute stepwise IOP elevation from 10 to 120 mmHg (5 mmHg steps each 3 minutes). IOP was then returned to baseline and recovery was monitored for 2 hours. Photopic electroretinograms (ERG) were recorded at each IOP step during stress and at each minute during recovery. Ocular blood flow and vitreal oxygen tension (pO2) were assayed continuously and simultaneously using a combined laser Doppler flow meter (LDF) and an oxygen sensitive fibre-optic probe, respectively. The combined sensor was placed in the vitreous chamber, proximal to the retina. Data were binned into 3 minute intervals during stress and 1 min intervals during recovery. Recovery data was described using a bi-logistic function. RESULTS: Rats of both ages showed similar susceptibility to IOP elevation, with pO2 showing a closer relationship to ERG than LDF. During recovery, both ages showed a distinctive two-phased recovery for all three measures with the exception of the LDF in 3-month-old rats, which showed only 1 phase. In all animals, LDF recovered fastest (<1 minute), followed by pO2 (<10 minute) and ERG (>1 hour). 14-month-old rats showed surprisingly faster and greater LDF recovery compared to the younger group, with similar levels of pO2 recovery. However, the ERG in these middle-aged animals did not fully recover after two hours, despite showing no difference in susceptibility to IOP during stress compared to the young group. CONCLUSIONS: Young and middle-aged eyes showed similar susceptibility to IOP elevation in terms of pO2, LDF and ERG. Despite this lack of difference during stress, older eyes did not completely recover function, suggesting a more subtle age-related susceptibility to IOP.
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ItemIncrease in mitochondrial DNA mutations impairs retinal function and renders the retina vulnerable to injury(WILEY, 2011-08)Mouse models that accumulate high levels of mitochondrial DNA (mtDNA) mutations owing to impairments in mitochondrial polymerase γ (PolG) proofreading function have been shown to develop phenotypes consistent with accelerated aging. As increase in mtDNA mutations and aging are risk factors for neurodegenerative diseases, we sought to determine whether increase in mtDNA mutations renders neurons more vulnerable to injury. We therefore examined the in vivo functional activity of retinal neurons and their ability to cope with stress in transgenic mice harboring a neural-targeted mutant PolG gene with an impaired proofreading capability (Kasahara, et al. (2006) Mol Psychiatry11(6):577-93, 523). We confirmed that the retina of these transgenic mice have increased mtDNA deletions and point mutations and decreased expression of mitochondrial oxidative phosphorylation enzymes. Associated with these changes, the PolG transgenic mice demonstrated accelerated age-related loss in retinal function as measured by dark-adapted electroretinogram, particularly in the inner and middle retina. Furthermore, the retinal ganglion cell-dominant inner retinal function in PolG transgenic mice showed greater vulnerability to injury induced by raised intraocular pressure, an insult known to produce mechanical, metabolic, and oxidative stress in the retina. These findings indicate that an accumulation of mtDNA mutations is associated with impairment in neural function and reduced capacity of neurons to resist external stress in vivo, suggesting a potential mechanism whereby aging central nervous system can become more vulnerable to neurodegeneration.
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ItemEffect of acute intraocular pressure challenge on rat retinal and cortical function(Association for Research in Vision and Ophthalmology (ARVO), 2014)Purpose: The global or gross response index of visual performance measured from the eye does not necessarily translate to global responses measured from the brain. A better understanding of this relationship would facilitate the monitoring of disease models that affect the visual pathway. We consider whether rod- and cone-retino-cortical-pathways are equally affected by acute IOP elevation. Methods: Acute, stepwise IOP elevation (10, 30, 40, 50, 60, 70 mm Hg) was induced in anesthetized dark- (N = 8) and light-adapted pigmented rats (N = 6). Electroretinogram (ERG) and visual evoked potentials (VEP) were simultaneously measured after 10 minutes at each step. Relative amplitudes (treated/baseline, %) as a function of IOP level were described with a cumulative normal function. Results: Our results showed decline in scotopic and photopic ERGs with IOP elevation. Photopic ERG responses were less sensitive to IOP challenge than scotopic ERG responses. Despite significant reductions of ganglion cell–mediated waveforms at 70 mm Hg, the VEP showed only subtle decreases in amplitude. Intraocular pressure elevation produced similar effects on rod- and cone-mediated VEP waveforms. Conclusions: We show that cone signals are less sensitive than rod ERGs to acute IOP challenge. Also, retinal signals are more sensitive than are cortical signals to IOP stress, suggesting that cortical processing may act to salvage reductions expected from attenuated retinal output.
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ItemSustained and Transient Contributions to the Rat Dark-Adapted Electroretinogram b-Wave(HINDAWI LTD, 2013)The most dominant feature of the electroretinogram, the b-wave, is thought to reflect ON-bipolar cell responses. However, a number of studies suggest that the b-wave is made up of several components. We consider the composition of the rat b-wave by subtracting corneal negative components obtained using intravitreal application of pharmacological agents to remove postreceptoral responses. By analyzing the intensity-response characteristic of the PII across a range of fixed times during and after a light step, we find that the rat isolated PII has 2 components. The first has fast rise and decay characteristics with a low sensitivity to light. GABAc-mediated inhibitory pathways enhance this transient-ON component to manifest increased and deceased sensitivity to light at shorter (<160 ms) and longer times, respectively. The second component has slower temporal characteristics but is more sensitive to light. GABAc-mediated inhibition enhances this sustained-ON component but has little effect on its sensitivity to light. After stimulus offset, both transient and sustained components return to baseline, and a long latency sustained positive component becomes apparent. The light sensitivities of transient-ON and sustained-OFF components are consistent with activity arising from cone ON- and OFF-bipolar cells, whereas the sustained-ON component is likely to arise from rod bipolar cells.