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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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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ItemNo Preview AvailableRetinal Oxygen Saturation: Novel Analysis Method for the Oxymap(LIPPINCOTT WILLIAMS & WILKINS, 2013-10)PURPOSE: To use a novel image analysis approach to consider how oxygen saturation changes as a function of vessel width and distance from the nerve and between superior and inferior retinal hemifields. METHODS: Ten images were acquired from one eye of 17 participants (mean [standard deviation] age, 28 [4] years; range, 22-38 years) using the Oxymap T1 retinal oximeter. Every pixel identified by the detection algorithm was extracted, and frequency histograms of retinal vessel oxygen saturation were plotted for each vessel diameter (70-170 μm). Histograms were fitted with two Gaussian models to identify peak arteriole and venule oxygen saturation. Mean (±standard error of the mean) arteriole and venule oxygen saturation at each vessel width were calculated. Data were also analyzed in (1) annuli of 100 μm centered on the optic nerve or (2) upper and lower hemifields demarcated by the center of the optic nerve. RESULTS: Venous oxygen saturation was higher in smaller vessels than in larger vessels. Arterial oxygen saturation remained relatively constant with vessel width. Oxygen saturation was lower in veins nearer the optic nerve. The upper retinal hemisphere showed higher venous oxygen saturation compared with the lower hemifield. CONCLUSIONS: The current objective analysis approach provides a more complete picture of retinal oxygen saturation at the posterior pole as a function of vessel width and retinal location.
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ItemRelationship between the Magnitude of Intraocular Pressure during an Episode of Acute Elevation and Retinal Damage Four Weeks later in Rats(PUBLIC LIBRARY SCIENCE, 2013-07-29)PURPOSE: To determine relationship between the magnitude of intraocular pressure (IOP) during a fixed-duration episode of acute elevation and the loss of retinal function and structure 4 weeks later in rats. METHODS: Unilateral elevation of IOP (105 minutes) was achieved manometrically in adult Brown Norway rats (9 groups; n = 4 to 8 each, 10-100 mm Hg and sham control). Full-field ERGs were recorded simultaneously from treated and control eyes 4 weeks after IOP elevation. Scotopic ERG stimuli were white flashes (-6.04 to 2.72 log cd.s.m(-2)). Photopic ERGs were recorded (1.22 to 2.72 log cd.s.m(-2)) after 15 min of light adaptation (150 cd/m(2)). Relative amplitude (treated/control, %) of ERG components versus IOP was described with a cummulative normal function. Retinal ganglion cell (RGC) layer density was determined post mortem by histology. RESULTS: All ERG components failed to recover completely normal amplitudes by 4 weeks after the insult if IOP was 70 mmHg or greater during the episode. There was no ERG recovery at all if IOP was 100 mmHg. Outer retinal (photoreceptor) function demonstrated the least sensitivity to prior acute IOP elevation. ERG components reflecting inner retinal function were correlated with post mortem RGC layer density. CONCLUSIONS: Retinal function recovers after IOP normalization, such that it requires a level of acute IOP elevation approximately 10 mmHg higher to cause a pattern of permanent dysfunction similar to that observed during the acute event. There is a 'threshold' for permanent retinal functional loss in the rat at an IOP between 60 and 70 mmHg if sustained for 105 minutes or more.
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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.
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ItemUsing the Electroretinogram to Understand How Intraocular Pressure Elevation Affects the Rat Retina(HINDAWI LTD, 2013)Intraocular pressure (IOP) elevation is a key risk factor for glaucoma. Our understanding of the effect that IOP elevation has on the eye has been greatly enhanced by the application of the electroretinogram (ERG). In this paper, we describe how the ERG in the rodent eye is affected by changes in IOP magnitude, duration, and number of spikes. We consider how the variables of blood pressure and age can modify the effect of IOP elevation on the ERG. Finally, we contrast the effects that acute and chronic IOP elevation can have on the rodent ERG.
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ItemSusceptibility of Streptozotocin-Induced Diabetic Rat Retinal Function and Ocular Blood Flow to Acute Intraocular Pressure Challenge(ASSOC RESEARCH VISION OPHTHALMOLOGY INC, 2013-03)PURPOSE: To consider the hypothesis that streptozotocin (STZ)-induced hyperglycemia renders rat retinal function and ocular blood flow more susceptible to acute IOP challenge. METHODS: Retinal function (electroretinogram [ERG]) was measured during acute IOP challenge (10100 mm Hg, increments of 5 mm Hg, 3 minutes per step, vitreal cannulation) in adult Long-Evans rats (6 weeks old; citrate: n = 6, STZ: n = 10) 4 weeks after citrate buffer or STZ (65 mg/kg, blood glucose >15 mM) injection. At each IOP, dim and bright flash (-4.56, -1.72 log cd x s x m(-2)) ERG responses were recorded to measure inner retinal and ON-bipolar cell function, respectively. Ocular blood flow (laser Doppler flowmetry; citrate: n = 6, STZ: n = 10) was also measured during acute IOP challenge. Retinas were isolated for quantitative PCR analysis of nitric oxide synthase mRNA expression (endothelial, eNos; inducible, iNos; neuronal, nNos). RESULTS: STZ-induced diabetes increased the susceptibility of inner retinal (IOP at 50% response, 60.1, CI: 57.0-62.0 mm Hg versus citrate: 67.5, CI: 62.1-72.4 mm Hg) and ON-bipolar cell function (STZ: 60.3, CI: 58.0-62.8 mm Hg versus citrate: 65.1, CI: 61.9-68.6 mm Hg) and ocular blood flow (43.9, CI: 40.8-46.8 versus citrate: 53.4, CI: 50.7-56.1 mm Hg) to IOP challenge. Citrate eyes showed elevated eNos mRNA (+49.7%) after IOP stress, an effect not found in STZ-diabetic eyes (-5.7%, P < 0.03). No difference was observed for iNos or nNos (P > 0.05) following IOP elevation. CONCLUSIONS: STZ-induced diabetes increased functional susceptibility during acute IOP challenge. This functional vulnerability is associated with a reduced capacity for diabetic eyes to upregulate eNos expression and to autoregulate blood flow in response to stress.
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ItemIncreased Susceptibility to Injury in Older Eyes(LIPPINCOTT WILLIAMS & WILKINS, 2013-03)PURPOSE: To determine whether there is an age-dependent susceptibility in retinal function in response to repeated anterior chamber cannulation with or without intraocular pressure (IOP) elevation. METHODS: Baseline electroretinograms were measured in 3- and 18-month-old Sprague-Dawley rats (n = 16 each group). Following baseline assessment, eyes were randomly assigned to undergo a 60-min anterior chamber cannulation with IOP either left at baseline (sham, 15 mm Hg) or elevated to 60 mm Hg. This was repeated three additional times, with each episode separated by 1 week. At weeks 1 to 3, dark-adapted retinal function was assessed immediately before cannulation, with final functional assessment at week 4. RESULTS: Both sham and IOP elevated eyes of older rats showed retinal dysfunction, which became more pronounced with the number of repeated insults. This effect was largest for responses arising from the inner retina. Repeated insult in younger eyes did not produce a change in amplitude but an increase in the sensitivity to light of photoreceptoral and bipolar cell components of the electroretinogram. CONCLUSIONS: Repeated trauma, not IOP, produces permanent retinal dysfunction in older eyes. Younger eyes appear to be able to withstand this type of injury by upregulating sensitivity of outer and middle retinal responses to maintain normal inner retinal function.
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ItemElectroretinography in streptozotocin diabetic rats following acute intraocular pressure elevation(SPRINGER, 2013-02)BACKGROUND: We consider whether pre-existing streptozotocin induced hyperglycemia in rats affects the ability of the eye to cope with a single episode of acute intraocular pressure (IOP) elevation. METHODS: Electroretinogram (ERG) responses were measured (-6.08 to 1.92 log cd.s.m(-2)) in anaesthetized (60:5 mg/kg ketamine:xylazine) dark-adapted (>12 h) adult Sprague-Dawley rats 1 week after a single acute IOP elevation to 70 mmHg for 60 min. This was undertaken in rats treated 11 weeks earlier with streptozotocin (STZ, n = 12, 50 mg/kg at 6 weeks of age) or citrate buffer (n = 12). ERG responses were analyzed to derive an index of photoreceptor (a-wave), ON-bipolar (b-wave), amacrine (oscillatory potentials) and inner retinal (positive scotopic threshold response, pSTR) function. RESULTS: One week following acute IOP elevation there was a significant reduction of the ganglion cell pSTR (-35 ± 11 %, P = 0.0161) in STZ-injected animals. In contrast the pSTR in citrate-injected animals was not significant changed (+16 ± 14 %). The negative component of the STR was unaffected by IOP elevation in either citrate or STZ-treated groups. Photoreceptoral (a-wave, citrate-control +4 ± 3 %, STZ +4 ± 5 %) and ON-bipolar cell (b-wave, control +4 ± 3 %, STZ +4 ± 5 %) mediated responses were not significantly affected by IOP elevation in either citrate- or STZ-injected rats. Finally, oscillatory potentials (citrate-control +8 ± 23 %, STZ +1 ± 17 %) were not reduced 1 week after IOP challenge. CONCLUSIONS: The ganglion cell dominated pSTR was reduced following a single episode of IOP elevation in STZ diabetic, but not control rats. These data indicate that hyperglycemia renders the inner retina more susceptible to IOP elevation.