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PURPOSE: The aim of this study was to determine the short-term compliance with regular home monitoring of macular retinal sensitivity (RS) in intermediate age-related macular degeneration (iAMD). Home-based outcomes were compared with in-clinic outcomes determined using (1) the same tablet device under supervision, and (2) the Macular Integrity Assessment (MaIA) microperimeter. DESIGN: Single-center longitudinal compliance and reliability study. METHODS: A total of 73 participants with iAMD were trained to perform macular field testing with the Melbourne Rapid Fields-macular (MRF-m) iPad application. Volunteers were asked to return 6 weekly tests from home, guided by audio instructions. We determined compliance with weekly testing and surveyed for factors that limited compliance. Test reliability (false positive, false negative) and RS were compared to in-clinic assays (MaIA). Data are given as mean ± SD or as median [quartile 1-3 range]. Group comparisons were achieved with bootstrap to define the 95% confidence limits. RESULTS: A total of 59 participants submitted 6 home examinations with a median intertest interval of 8.0 [7.0-17] days. Compliance with weekly testing (7 days ±24 hours) was 55%. The main barrier to compliance was information technology (IT) logistic reasons. Of 694 home examinations submitted, 96% were reliable (false-positive results <25%). The mean RS returned by the tablet was significantly higher (+3.2 dB, P < .05) compared to the MaIA. CONCLUSIONS: Home monitoring produces reliable results that differ from in-clinic tests because of test design. This should not affect self-monitoring once an at-home baseline is established, but these differences will affect comparisons with in-clinic outcomes. Reasonable compliance with weekly testing was achieved. Improved IT support might lead to better compliance.

BACKGROUND: As measurable sensory and motor deficits are key to the diagnosis of stroke, we investigated the value of objective tablet based vision and visuomotor capacity assessment in acute mild-moderate ischemic stroke (AIS) patients. METHODS: Sixty AIS patients (65 ± 14 years, 33 males) without pre-existing visual/neurological disorders and acuity better than 6/12 were tested at their bedside during the first week post-stroke and were compared to 40 controls (64 ± 11 years, 15 males). Visual field sensitivity, quantified as mean deviation (dB) and visual acuity (with and without luminance noise), were tested on MRFn (Melbourne Rapid Field-Neural) iPad application. Visuomotor capacity was assessed with the Lee-Ryan Eye-Hand Coordination (EHC) iPad application using a capacitive stylus for iPad held in the preferred hand.Time to trace 3 shapes and displacement errors (deviations of >3.5 mm from the shape) were recorded. Diagnostic capacity was considered with Receiver Operating Characteristics. Vision test outcomes were correlated with National Institutes of Health Stroke Scale (NIHSS) score at the admission. RESULTS: Of the 60 AIS patients, 58 grasped the iPad stylus in their preferred right hand even though 31 had left hemisphere lesions. Forty-one patients (68%) with better than 6/12 visual acuity (19 right, 19 left hemisphere and 3 multi-territorial lesions) returned significantly abnormal visual fields. The stroke group took significantly longer (AIS: 93.4 ± 60.1 s; Controls: 33.1 ± 11.5 s, p < 0.01) to complete EHC tracing and made larger displacements (AIS: 16,388 ± 36,367 mm; Controls: 2,620 ± 1,359 mm, p < 0.01) although both control and stroke groups made similar numbers of errors. EHC time was not significantly different between participants with R (n = 26, 84.3 ± 55.3 s) and L (n = 31, 101.3 ± 64.7 s) hemisphere lesions. NIHSS scores and EHC measures showed low correlations (Spearman R: -0.15, L: 0.17). ROC analysis of EHC and vision tests found high d

Background: Our primary aim is to quantify test reliability and compliance of glaucoma patients to a weekly visual field telemedicine (VFTM) schedule. A secondary aim is to determine concordance of the VFTM results to in-clinic outcomes. Methods: Participants with stable glaucoma in one eye were recruited for a 12 month VFTM trial using the Melbourne Rapid Fields (MRF-home, MRFh) iPad application. Participants attended routine 6 month clinical reviews and were tasked with weekly home monitoring with the MRFh over this period. We determined compliance to weekly VFTM (7 + 1 days) and test reliability (false positives (FPs) and fixation loss (FL) <33%). A secondary aim considered concordance to in-clinic measures of visual field (MRF-clinic (MRFc) and the Humphrey Field Analyzer (HFA)) in active participants (≥10 home examinations and 5 reliable HFA examinations). The linear trend in the MRFh mean deviation (MD) was compared to the HFA guided progression analysis (GPA) using Bland−Altman methods. Data are shown as the mean ± standard deviation. Results: Forty-seven participants with a mean age of 64 ± 14.6 years were recruited for the trial. The VFTM uptake was 85% and compliance to weekly home monitoring was 75% in the presence of weekly text reminders in the analysed group (n = 20). The analysed group was composed of test subjects with five reliable in-clinic HFA examinations (GPA analysis available) and who submitted a minimum of 10 MRFh examinations from home. Of the 757 home examinations returned, approximately two-thirds were reliable, which was significantly lower than the test reliability of the HFA in-clinic (MRFh: 65% vs. HFA: 85%, p < 0.001). The HFA-GPA analysis gave little bias from the MRFh slope (bias: 0.05 dB/yr, p > 0.05). Two eyes were found to have clinical progression during the 12 month period, and both were detected by VFTM. Conclusions: VFTM over 12 months returned good compliance (75%) to weekly testing with good concordance to in-clinic assays.

AIM AND OBJECTIVE: Developing improved methods for early detection of visual field defects is pivotal to reducing glaucoma-related vision loss. The Melbourne Rapid Fields screening module (MRF-S) is an iPad-based test, which allows suprathreshold screening with zone-based analysis to rapidly assess the risk of manifest glaucoma. The versatility of MRF-S has potential utility in rural areas and during infectious pandemics. This study evaluates the utility of MRF-S for detecting field defects in non-metropolitan settings. MATERIALS AND METHODS: This was a prospective, multicenter, cross-sectional validation study. Two hundred and fifty-two eyes of 142 participants were recruited from rural sites through two outreach eye services in Australia. Participants were tested using MRF-S and compared with a reference standard; either Zeiss Humphrey Field Analyzer or Haag-Streit Octopus performed at the same visit. Standardized questionnaires were used to assess user acceptability. Major outcome measures were the area under the curve (AUC) for detecting mild and moderate field defects defined by the reference tests, along with corresponding performance characteristics (sensitivity, specificity). RESULTS: The mean test duration for MRF-S was 1.88 minutes compared with 5.92 minutes for reference tests. The AUCs for mild and moderate field defects were 0.81 [95% confidence interval (CI): 0.75-0.87] and 0.87 (95% CI: 0.83-0.92), respectively, indicating very good diagnostic accuracy. Using a risk criterion of 55%, MRF-S identified moderate field defects with a sensitivity and specificity of 88.4 and 81.0%, respectively. CONCLUSION AND CLINICAL SIGNIFICANCE: The MRF-S iPad module can identify patients with mild and moderate field defects while delivering favorable user acceptability and short test duration. This has potential application within rural locations and amidst infectious pandemics. HOW TO CITE THIS ARTICLE: Chia MA, Trang E, Agar A, et al. Screening for Glaucomatous Visua

PURPOSE: This study examines the short-term uptake, compliance, and performance of a tablet device used for home monitoring of visual field (VF-Home) by glaucoma patients. DESIGN: Single-center, observational, longitudinal, compliance study. METHODS: Participants who were glaucoma suspects or had stable glaucoma in at least one eye were recruited during a regular clinic review. Baseline in-clinic visual field (VF) was recorded with the Humphrey Field Analyser (HFA, SITA standard) and repeated at 6 months. Participants were tasked with performing 6 VF examinations from home, at weekly intervals, using a loaned iPad tablet. Uptake was defined as returning at least 1 test from home. Reliability and global indices from VF-Home were compared to in-clinic outcomes. Data are shown as either mean ± [standard deviation] or median [quartile 1-3 range], and group comparisons were achieved with bootstrap. RESULTS: We recruited 186 eyes of 101 participants. VF-Home uptake was excellent, with 88% of participants successfully completing ≥1 home examination and 69% completing all 6 examinations. The median duration between tests was 7.0 [7.0-8.0] days. Barriers to uptake and compliance involved information technology (IT) logistical reasons, lack of motivation, or competing life demands. VF-Home gave greater fixation loss but a similar level of False Positives (FP) as the HFA. A high correlation was found for the mean defect between in-clinic and at-home outcomes (R = 0.85). CONCLUSIONS: VF-Home can return a high level of short-term compliance and results comparable to those found by in-clinic testing. IT logistical reasons and lack of motivation are barriers to uptake and compliance.

The conventional stimulus for standard automated perimetry is fixed in size, giving elevated contrast thresholds and reduced test reliability in the periphery. Here, we test the hypothesis that appropriate scaling of the size of perimetric stimuli will return fixed thresholds and reduced variability across the visual field. We derived frequency-of-seeing (FOS) curves in five healthy subjects at central (3 degrees) and peripheral (27 degrees) locations with a method of constant stimuli (MOCS) using a desktop LCD display. FOS curves for a Goldmann III (GIII) stimulus were compared with those for size scaled spots. To consider clinical translation, we tested a further five healthy subjects (22-24 years) with the Melbourne Rapid Fields (MRF) tablet perimeter at several locations spanning 1 degree to 25 degrees from fixation, deriving FOS curves (MOCS) and also conducting repeated adaptive clinical thresholding to assess intra- and interobserver variability. We found that GIII contrast thresholds were significantly elevated in the periphery compared with the parafovea, with concomitant reduction of FOS slope. Using appropriately size scaled spots, threshold and slope differences between these locations were significantly reduced. FOS data collected with the tablet perimeter confirmed that size scaling confers broad equivalence of the shape of the FOS curve across the visual field. Repeated adaptive thresholding with size scaled stimuli gave relatively constant intra-observer variability across the visual field, which compares favorably with published normative data obtained with the GIII stimulus. The reduced variability will improve signal-to-noise ratio for correct classification of normal visual field test results, whereas the lower contrast thresholds yield greater dynamic range, which should improve the ability to reliably monitor moderate defects.

Most clinical diagnoses of stroke are based on the persistence of symptoms relating to consciousness, language, visual-field loss, extraocular movement, neglect (visual), motor strength, and sensory loss following acute cerebral infarction. Yet despite the fact that most motor actions and cognition are driven by vision, functional vision per se is seldom tested rigorously during hospitalization. Hence we set out to determine the effects of acute stroke on functional vision, using an iPad application (Melbourne Rapid Field-Neural) that can be used to assess vision (visual acuity and visual field sensitivity) at the bedside or in the emergency ward in about 6 min per eye. Our convenience sample comprised 60 (29-88 years, 65 ± 14 years, 33 males) of 160 sequentially presenting first episode, acute (<7 days) ischemic stroke patients at Sunshine Hospital, Melbourne. One hundred patients were excluded due to existing eye disease, inadequate radiological confirmation, inability to comply with English directions or too ill to participate. Stroke cases were compared with 37 (29-85 years, 64 ± 12 years,14 males) similar-aged controls using a Mann-Whitney U-test. A significant loss in visual field sensitivity was measured in 68% of stroke cases (41/60, Mean Deviation: Stroke: -5.39 ± 6.26 dB, Control: 0.30 ± 0.60 dB, MWU = 246, p < 0.0001). Surprisingly, 44% (18/41) of these patients were unaware of their field loss. Although high contrast visual acuity was unaffected in most (55/60) patients, visual acuity-in-noise was reduced in 62% (37/60, Stroke: mean 6/12-2, log MAR 0.34 ± 0.21 vs. Control: mean 6/7·5-2, log MAR 0.14 ± 0.10; MWU = 470, p < 0.0001). Visual field defects were associated with all occipital, parietal and posterior cerebellar artery strokes while 9/15 middle cerebral artery lesions and 11 lesions in other brain regions were also associated with visual field defects. Our findings demonstrate that ~2/3 of acute first episode ischemic stroke patients experience a

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.

PURPOSE. The purpose of this study was to test the hypothesis that the superficial, intermediate, and deep retinal vascular plexus show different responses to intraocular pressure (IOP) elevation. METHODS. Anesthetized adult Long Evans rats (n = 14) were imaged using optical coherence tomography angiography (OCTA; Spectralis) at baseline (IOP 10 mm Hg) and in follow-up mode to examine the vasculature during IOP elevation (10 to 110 mm Hg, 10 mm Hg steps, each step 3 minutes). A 20° × 10° field was imaged. Vessel density within a 2D projection image was determined (%) for the superficial vascular complex (SVC), intermediate capillary plexus (ICP), and deep capillary plexus (DCP). Comparisons were made between layers using 2-way repeated measures ANOVA (layer versus IOP) following normalization to baseline (% relative to 10 mm Hg). RESULTS. The three vascular layers responded differently to IOP elevation. For IOPs between 40 and 60 mm Hg, DCP and ICP capillaries were significantly more resistant to IOP elevation than those in the SVC. When IOP was elevated above 70 mm Hg, all layers showed reduced vessel density. IOP induced change in SVC vessel density closely followed reductions in thickness of the inner retinal layers (nerve fiber, ganglion cell, and inner plexiform layer). This close relationship between reductions in tissue thickness and vessel density was less apparent for the ICP and DCP. CONCLUSIONS. These data show that the intermediate and deep vascular plexus in the rat retina have a greater capacity for autoregulation against mild IOP elevation but are more affected at high IOP.

Purpose : The retina, an accessible outpouching of the central nervous system, may manifest cortical changes that occur with Parkinson’s disease (PD), lending itself as a potential biomarker. PD is characterised by reduced dopamine levels, a neurotransmitter found in amacrine cells. Human PD patients have also shown structural changes in the outer retina. This work aims to determine if retinal function and structure are altered in a murine model of PD and whether deficits can be ameliorated with L-DOPA treatment. Methods : A PD model was induced in adult C57BL6/J mice using MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, 4x i.p. injections, 20mg/kg) and vehicle control and examined at day 21 and 45. Another MPTP group was administered L-DOPA (L-3,4-dihydroxyphenylalanine 0.2 mg/ml) or control in their drinking water and assessed at day 45 (n=12–15/group). In ketamine:xylazine anaesthetised (80:10mg/kg) mice full-field dark- and light-adapted electroretinography (ERG) was assessed to target dopamine-related responses. Optical coherence tomography (OCT) was used to quantify thickness of retinal layers. Retinal and cortical tissue were collected for immunohistochemical assessment of changes in tyrosine hydroxylase (TH)and imaged using confocal microscopy. Data (mean±SEM) were compared using unpaired ANOVA and t-tests as appropriate. Results : At day 21 no retinal changes were found. At day 45 dark and light adapted ERGs showed slower amacrine cell responses (oscillatory potential, p<0.05), a finding which reversed with L-DOPA treatment (p<0.05). Other components of the ERG were unchanged. TH staining showed a trend towards decreased retinal levels in MPTP mice but this did not reach significance (p=0.10). Reduced levels of TH were found in the ventral hippocampus of MPTP mice compared with control (p<0.05). OCT revealed thinning of the outer plexiform layer at day 45, and the L-DOPA group exhibited a thinning of the outer nuclear layer (p<0.05). Conclusions : This

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].

PURPOSE: Aging and glaucoma both result in contrast processing deficits. However, it is unclear the extent to which these functional deficits arise from retinal or post-retinal neuronal changes. This study aims to disentangle the effects of healthy human aging and glaucoma on retinal and post-retinal contrast processing using visual electrophysiology. METHODS: Steady-state pattern electroretinograms (PERG) and pattern visual evoked potentials (PVEP) were simultaneously recorded across a range of contrasts (0%, 4%, 9%, 18%, 39%, 73%, 97%; 0.8° diameter checks, 31° diameter checkerboard) in 13 glaucoma patients (67 ± 6 years), 15 older (63 ± 8 years) and 14 younger adults (27 ± 3 years). PERG and PVEP contrast response functions were fit with a linear and saturating hyperbolic model, respectively. PERG and PVEP magnitude, timing (phase), and model fit parameters (slope, semi-saturation constant) were compared between groups. RESULTS: PERG responses were reduced and delayed in older adults relative to younger adults, and further reduced and delayed in glaucoma patients across all contrasts. PVEP signals were also reduced and delayed in glaucoma patients, relative to age-similar (older) controls. However, despite having reduced PERG magnitudes, older adults did not demonstrate reduced PVEP magnitudes. CONCLUSIONS: Older adults with healthy vision demonstrate reduced magnitude and delayed timing in the PERG that is not reflected in the PVEP. In contrast, glaucoma produces functional deficits in both PERG and PVEP contrast response functions. Our results suggest that glaucomatous effects on contrast processing are not a simple extension of those that arise as part of the aging process.

PURPOSE: To investigate the ocular inflammatory response, using clinical and immunological techniques, in people experiencing contact lens (CL) discomfort. METHODS: This study involved 38 adults who were full-time, silicone-hydrogel CL wearers. Participants were categorized into groups based upon a validated CL dry-eye questionnaire (CLDEQ-8) (n = 17 'asymptomatic', CLDEQ-8 score <9; n = 21 'symptomatic', CLDEQ-8 score ≥13). Examinations were performed at two visits (one with, and one without, CL wear), separated by one-week. Testing included: tear osmolarity, ocular redness, tear stability, ocular surface staining, meibography, tear production and tear collection. Tear osmolarity was taken from the inferior-lateral and superior-lateral menisci. The 'Inferior-Superior Osmotic Difference', I-SOD, was the absolute osmolarity difference between these menisci. Concentrations of seven cytokines (IL-2, IL-4, IL-6, IL-10, IL-17A, IFN-gamma, TNF-alpha) were assayed from basal tears using multiplex cytometric bead array. RESULTS: At baseline, there was no significant difference in key clinical signs between asymptomatic and symptomatic CL wearers (p > 0.05). The I-SOD was greater in symptomatic than asymptomatic CL wearers (23.1 ± 2.6 versus 11.3 ± 1.4 mOsmol/L, p = 0.001). People experiencing CL discomfort had higher tear IL-17A (122.6 ± 23.7 versus 44.0 ± 10.0 pg/mL, p = 0.02) and reduced tear stability (6.3 ± 1.1 versus 10.4 ± 1.6 s, p = 0.03) after several hours of CL wear. Tear IL-17A levels correlated with both the I-SOD (r = 0.43, p = 0.01) and CLDEQ-8 score (r = 0.40, p = 0.01). CONCLUSIONS: CL discomfort occurs in individuals having no clinical dry eye signs, and is associated with higher tear levels of the pro-inflammatory cytokine IL-17A. These findings support an association between the discomfort response and low-grade, ocular surface inflammation.

PURPOSE: To test the hypothesis that the capacity for retinal ganglion cells to functionally recover from chronic IOP elevation is dependent on the duration of IOP elevation. METHODS: IOP elevation was induced in one eye in anesthetized (isoflurane) adult C57BL6/J mice using a circumlimbal suture. Sutures were left in place for 8 and 16 weeks (n = 30 and 28). In two other groups the suture was cut after 8 and 12 weeks (n = 30 and 28), and ganglion cell function (electroretinography) and retinal structure (optical coherence tomography) were assessed 4 weeks later. Ganglion cell density was quantified by counting RBPMS (RNA-binding protein with multiple splicing)-stained cells. RESULTS: With IOP elevation (∼10 mm Hg above baseline), ganglion cell function declined to 75% ± 8% at 8 weeks and 59% ± 4% at 16 weeks relative to contralateral control eyes. The retinal nerve fiber layer was thinner at 8 (84% ± 4%) and 16 weeks (83% ± 3%), without a significant difference in total retinal thickness. Ganglion cell function recovered with IOP normalization (suture removal) at week 8 (97% ± 7%), but not at week 12 (73% ± 6%). Ganglion cell loss was found in all groups (-8% to -13%). CONCLUSIONS: In the mouse circumlimbal suture model, 12 weeks of IOP elevation resulted in irreversible ganglion cell dysfunction, whereas retinal dysfunction was fully reversible after 8 weeks of IOP elevation.

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 c

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.

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.

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.

Background Several visual tasks have been proposed as indirect assays of the balance between cortical inhibition and excitation in migraine. This study aimed to determine whether daily measurement of performance on such tasks can reveal perceptual changes in the build up to migraine events. Methods Visual performance was measured daily at home in 16 non-headache controls and 18 individuals with migraine using a testing protocol on a portable tablet device. Observers performed two tasks: luminance increment detection in spatial luminance noise and centre surround contrast suppression. Results Luminance thresholds were reduced in migraine compared to control groups ( p < 0.05), but thresholds did not alter across the migraine cycle; while headache-free, centre-surround contrast suppression was stronger for the migraine group relative to controls ( p < 0.05). Surround suppression weakened at around 48 hours prior to a migraine attack and strengthened to approach their headache-free levels by 24 hours post-migraine (main effect of timing, p < 0.05). Conclusions Daily portable testing of vision enabled insight into perceptual performance in the lead up to migraine events, a time point that is typically difficult to capture experimentally. Perceptual surround suppression of contrast fluctuates during the migraine cycle, supporting the utility of this measure as an indirect, non-invasive assay of the balance between cortical inhibition and excitation.

BACKGROUND: In the assessment of a pituitary mass, objective visual field testing represents a valuable means of evaluating mass effect, and thus in deciding whether surgical management is warranted. CASE PRESENTATION: In this vignette, we describe a 73 year-old lady who presented with a three-week history of frontal headache, and 'blurriness' in the left side of her vision, due to a WHO grade III anaplastic haemangiopericytoma compressing the optic chiasm. We report how timely investigations, including an iPad-based visual field test (Melbourne Rapid Field, (MRF)) conducted at the bedside aided swift and appropriate management of the patient. CONCLUSIONS: We envisage such a test having a role in assessing bed-bound patients in hospital where access to formal visual field testing is difficult, or indeed in rapid testing of visual fields at the bedside to screen for post-operative complications, such as haematoma.

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.

To consider whether a circumlimbal suture can be used to chronically elevate intraocular pressure (IOP) in mice and to assess its effect on retinal structure, function and gene expression of stretch sensitive channels. Anesthetized adult C57BL6/J mice had a circumlimbal suture (10/0) applied around the equator of one eye. In treated eyes (n = 23) the suture was left in place for 12 weeks whilst in sham control eyes the suture was removed at day two (n = 17). Contralateral eyes served as untreated controls. IOP was measured after surgery and once a week thereafter. After 12 weeks, electroretinography (ERG) was performed to assess photoreceptor, bipolar cell and retinal ganglion cell (RGC) function. Retinal structure was evaluated using optical coherence tomography. Retinae were processed for counts of ganglion cell density or for quantitative RT-PCR to quantify purinergic (P2x7, Adora3, Entpd1) or stretch sensitive channel (Panx1, Trpv4) gene expression. Immediately after suture application, IOP spiked to 33 ± 3 mmHg. After 1 day, IOP had recovered to 27 ± 3 mmHg. Between weeks 2 and 12, IOP remained elevated above baseline (control 14 ± 1 mmHg, ocular hypertensive 19 ± 1 mmHg). Suture removal at day 2 (Sham) restored IOP to baseline levels, where it remained through to week 12. ERG analysis showed that 12 weeks of IOP elevation reduced photoreceptor (-15 ± 4%), bipolar cell (-15 ± 4%) and ganglion cell responses (-19 ± 6%) compared to sham controls and respective contralateral eyes (untreated). The retinal nerve fiber layer was thinned in the presence of normal total retinal thickness. Ganglion cell density was reduced across all quadrants (superior -12 ± 5%; temporal, -7% ± 2%; inferior -9 ± 4%; nasal -8 ± 5%). Quantitative RT-PCR revealed a significant increase in Entpd1 gene expression (+11 ± 4%), whilst other genes were not significantly altered (P2x7, Adora3, Trpv4, Panx1). Our results show that circumlimbal ligation produces mild chronic ocular hypertension an

PURPOSE: To determine the correlation between the perimetric outcomes from perimetry software Melbourne Rapid Fields (MRF) run on an Apple iPad tablet and those from the Humphrey Field Analyzer (HFA). METHODS: The MRF software was designed with features including variable fixation and fast thresholding using Bayes logic. Here, we report a cross-sectional study on 90 eyes from 90 participants: 12 had normal optic nerves and 78 had glaucoma with various degrees of visual field loss (41 mild and 37 moderate-severe). Exclusion criteria were patients with worse than 20/40 vision or recent intraocular surgery. The visual field outcomes of MRF were compared against those returned from the HFA 24-2 SITA standard. Participants were tested twice on the MRF to establish test-retest repeatability. RESULTS: The test durations were shorter on MRF than HFA (5.7 ± 0.1 vs. 6.3 ± 0.1 minutes, P < 0.001). MRF showed a high level of concordance in its outcomes with HFA (intraclass coefficient [ICC] = 0.93 for mean defect [MD] and 0.86 for pattern deviation [PD]) although the MRF tended to give a less negative MD (1.4 dB bias) compared with the HFA. MRF also showed levels of test-retest reliability comparable to HFA (ICC = 0.93 for MD and 0.89 for PD, 95% limits of agreement -4.5 to 4.3 dB). CONCLUSION: The perimetry results from the MRF have a strong correlation to the HFA outcomes. MRF also has test-retest reliability comparable to HFA. TRANSLATIONAL RELEVANCE: Portable tablet perimetry may allow accurate assessment of visual field when standard perimetry machines are unavailable or unsuitable.

The electroretinogram (ERG) and visual evoked potential (VEP) are commonly used to assess the integrity of the visual pathway. The ERG measures the electrical responses of the retina to light stimulation, while the VEP measures the corresponding functional integrity of the visual pathways from the retina to the primary visual cortex following the same light event. The ERG waveform can be broken down into components that reflect responses from different retinal neuronal and glial cell classes. The early components of the VEP waveform represent the integrity of the optic nerve and higher cortical centers. These recordings can be conducted in isolation or together, depending on the application. The methodology described in this paper allows simultaneous assessment of retinal and cortical visual evoked electrophysiology from both eyes and both hemispheres. This is a useful way to more comprehensively assess retinal function and the upstream effects that changes in retinal function can have on visual evoked cortical function.

Migraine is a common and debilitating primary headache disorder that affects 10-15% of the general population, particularly people of working age. Migraine is relevant to providers of clinical eye-care because migraine attacks are associated with a range of visual sensory symptoms, and because of growing evidence that the results of standard tests of visual function necessary for the diagnosis and monitoring of glaucoma (visual fields, electrophysiology, ocular imaging) can be abnormal due to migraine. These abnormalities are measureable in-between migraine events (the interictal period), despite patients being asymptomatic and otherwise healthy. This picture is further complicated by epidemiological data that suggests an increased prevalence of migraine in patients with glaucoma, particularly in patients with normal tension glaucoma. We discuss how migraine, as a co-morbidity, can confound the results and interpretation of clinical tests that form part of contemporary glaucoma evaluation, and provide practical evidence-based recommendations for the clinical testing and management of patients with migraine who attend eye-care settings.

BACKGROUND: People with migraine show increased surround suppression of perceived contrast, a perceptual analogue of centre-surround antagonistic interactions in visual cortex. A proposed mechanism is that cortical 'hyperexcitability' or 'hyperresponsivity', a prominent theory in the migraine literature, drives abnormal excitatory-inhibitory balance to give increased local inhibition. The purpose of this cross-sectional study was to determine whether cortical hyperresponsivity and excitatory-inhibitory imbalance manifests in the visual cortical response of migraine sufferers. METHODS: Interictal steady-state visual evoked potentials (VEPs) in response to 0 to 97% contrast were recorded in 30 migraine participants (15 without aura, 15 with aura) and 21 non-headache controls. Monotonicity indices were calculated to determine response saturation or supersaturation. Contrast gain was modelled with a modified saturating hyperbolic function to allow for variation in excitation and inhibition. RESULTS: A greater proportion of migraine participants (43%) than controls (14%) exhibited significant VEP supersaturation at high contrast, based on monotonicity index (chi-square, p = 0.028). Supersaturation was also evident by the trend for greater suppressive exponent values in migraine compared to control individuals (Mann-Whitney rank sum, p = 0.075). CONCLUSIONS: Supersaturation in migraine is consistent with excess excitation (hyperresponsivity) driving increased network inhibition and provides support for excitatory-inhibitory imbalance as a pathophysiological disturbance in migraine.

Objective. To examine whether retinal electrophysiology is a useful surrogate marker of drug penetrance into the central nervous system (CNS). Materials and Methods. Brain and retinal electrophysiology were assessed with full-field visually evoked potentials and electroretinograms in conscious and anaesthetised rats following systemic or local administrations of centrally penetrant (muscimol) or nonpenetrant (isoguvacine) compounds. Results. Local injections into the eye/brain bypassed the blood neural barriers and produced changes in retinal/brain responses for both drugs. In conscious animals, systemic administration of muscimol resulted in retinal and brain biopotential changes, whereas systemic delivery of isoguvacine did not. General anaesthesia confounded these outcomes. Conclusions. Retinal electrophysiology, when recorded in conscious animals, shows promise as a viable biomarker of drug penetration into the CNS. In contrast, when conducted under anaesthetised conditions confounds can be induced in both cortical and retinal electrophysiological recordings.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder resulting in dementia and eventual death. It is the leading cause of dementia and the number of cases are projected to rise in the next few decades. Pathological hallmarks of AD include the presence of hyperphosphorylated tau and amyloid protein deposition. Currently, these pathological biomarkers are detected either through cerebrospinal fluid analysis, brain imaging or post-mortem. Though effective, these methods are not widely available due to issues such as the difficulty in acquiring samples, lack of infrastructure or high cost. Given that the eye possesses clear optics and shares many neural and vascular similarities to the brain, it offers a direct window to cerebral pathology. These unique characteristics lend itself to being a relatively inexpensive biomarker for AD which carries the potential for wide implementation. The development of ocular biomarkers can have far implications in the discovery of treatments which can improve the quality of lives of patients. In this review, we consider the current evidence for ocular biomarkers in AD and explore potential future avenues of research in this area.

PURPOSE: The aim of this study was to compare the self-reported clinical practice behaviours of optometrists in Australia and the United Kingdom (UK) with respect to the diagnosis and management of dry eye disease (DED). We also sought to examine whether the reported practices of clinicians in each region were consistent with current evidence-based recommendations for DED. METHODS: An online survey was distributed to optometrists (Australia, n = 654; UK, n = 1006). Respondents provided information about practice modality, years of optometric experience, preferred diagnostic and management strategies (stratified by DED severity) and the information/evidence base used to guide patient care. RESULTS: A total of 317 completed surveys were received (response rates, Australia: 21%, UK: 17%). Optometrists in both regions demonstrated similarly strong knowledge of tear film assessment and adopted both subjective and objective techniques to diagnose DED. Patient symptoms were considered the most important, valuable and commonly performed assessment by both Australian and UK respondents. UK practitioners valued and utilised conjunctival signs and tear meniscus height assessments more than Australian optometrists (p < 0.05), who placed relatively greater emphasis on sodium fluorescein tear break-up time to diagnose DED (p < 0.05). Clinicians in both locations tailored DED therapy to severity. While practitioners in both regions predominantly managed mild DED with eyelid hygiene and tear supplementation, Australian optometrists indicated prescribing topical corticosteroid therapy significantly more often than UK practitioners for moderate (14% vs 6%) and severe (52% vs 8%) disease (p < 0.05). The major source of information used to guide practitioners' dry eye management practices was continuing education conferences. CONCLUSIONS: This study highlights a range of parallels and divergences in dry eye clinical practice between Australian and UK optometrists. Our data identify bot

PURPOSE: To describe a tangent perimeter developed on an Apple iPad (Melbourne Rapid Field, MRF). METHODS: The MRF assays 66 locations over 28° × 18° by having the patient vary fixation. Spot size and background luminance are paired to yield constant thresholds across the field. Spot locations were selected after analysis of 360 patient records. The capacity of the MRF to detect defects was verified in five participants (age 22-28 years) by simulating four common losses: central, arcuate, quadrant, and hemianopia. We also consider the effect of: myosis, blur (+3 DS), viewing distance (25-75 cm), ambient light (4-600 lux), and retest repeatability (1-week apart) on thresholds. Group means [SEM] are compared by Student's t-test and repeatability returned from Bland-Altman analysis. RESULTS: We found a 5 cd.m-2 background replicates the Weber fraction produced by a Humphrey spot shown at 35 dB. Our variable size gives constant thresholds (29.6 [0.2] dB) across all locations. Altering viewing distance (25 cm = 29.8 [0.9] dB; 75 cm = 28.9 [0.6] dB) and ambient lighting (4 lux, 29.8 [0.8] dB; 600 lux, 29.5 [1.0] dB) did not affect threshold although screen reflections must be avoided. Myosis (-1.2 dB) and blur (-1.5 dB) will reduce sensitivity (P < 0.05). Simulated defects with a mean defect (MD) of -3.3 dB are detected by the MRF. The Coefficient of repeatability was 9.6% (SD ∼2.9 dB) in normal regions and 48.1% (SD ∼8.0 dB) in areas of simulated scotoma. CONCLUSIONS: Tablet technology can return efficient and reliable thresholds to 30° as a tangent perimeter. TRANSLATIONAL RELEVANCE: The MRF will allow testing at a bedside, at home, in rural or remote areas, or where equipment cannot be financed.

An increasing number of studies indicate that the optic nerve head of the eye is sensitive not only to changes in intraocular pressure (IOP), but also to intracranial pressure (ICP). This study examines changes to optic nerve and retinal structure in a rat model in response to a range of IOP and ICP levels using optical coherence tomography. Furthermore, we examine the functional sequelae of these structural changes by quantifying the effect of pressure changes on the electroretinogram. IOP elevation (10-90 mmHg) induces progressive deformation of the optic nerve head and retinal surface (P < 0.05), compression of the retina (P < 0.05) and bipolar cell (b-wave), and retinal ganglion cell (scotopic threshold response) dysfunction (P < 0.05). Simultaneously altering ICP (-5 to 30 mmHg) modifies these IOP-induced responses, with lower ICP (-5 mmHg) exacerbating and higher ICP (15-30 mmHg) ameliorating structural and functional deficits. Thus, the balance between IOP and ICP (optic nerve pressure gradient, ONPG = IOP - ICP) plays an important role in optic nerve integrity. Structural and functional parameters exhibit a two-phase relationship to ONPG, with structural changes being more sensitive to ONPG modification (threshold = -0.6 to 11.3 mmHg) compared with functional changes (threshold = 49.7-54.6 mmHg). These findings have implications for diseases including glaucoma, intracranial hypertension, and long-term exposure to microgravity.

PURPOSE: To induce chronic intraocular pressure (IOP) elevation in rat eyes by circumlimbal suture. METHODS: Anesthetized (isoflurane) Long-Evans rats underwent unilateral circumlimbal suture implantation while the fellow eyes served as untreated controls (n = 15). A sham group (n = 8) received the same procedure except that the suture was loosely tied. Intraocular pressure, electroretinography (ERG), and optical coherence tomography (OCT) were monitored for 15 weeks, after which retinal histology and immunofluorescence staining for glial fibrillary acidic protein (GFAP) and ionized calcium binding adapter molecule-1 (Iba-1) were undertaken. RESULTS: Both IOP and ERG remained unaltered in the sham and all control eyes over 15 weeks. In the ocular hypertensive eye, IOP spiked from 17 ± 1 to 58 ± 3 mm Hg immediately after suture application, recovering to 32 ± 2 mm Hg by 24 hours, and remained elevated by 7 to 10 mm Hg above baseline for 15 weeks. At week 2, there was a small reduction of ERG components involving the photoreceptor a-wave, bipolar cell b-wave, and ganglion cell-mediated scotopic threshold response (pSTR). The reduction in a- and b-wave remained stable, while the pSTR became more affected from week 8 onward (P < 0.05). By week 12, there was progressive retinal nerve fiber layer (RNFL) thinning. At week 15, GFAP expression was upregulated in inner retina and on Müller cells. The ganglion cell dysfunction was associated with RNFL thinning and cell loss in the ganglion cell layer. CONCLUSIONS: Circumlimbal suture provides a simple and cost-effective way to induce mild chronic ocular hypertension in rat eyes. This model produces preferential ganglion cell dysfunction and RNFL reduction.

Age-related macular degeneration (AMD) is the leading cause of substantial and irreversible vision loss amongst elderly populations in industrialized countries. The advanced neovascular (or "wet") form of the disease is responsible for severe and aggressive loss of central vision. Current treatments aim to seal off leaky blood vessels via laser therapy or to suppress vessel leakage and neovascular growth through intraocular injections of antibodies that target vascular endothelial growth factor (VEGF). However, the long-term success of anti-VEGF therapy can be hampered by limitations such as low or variable efficacy, high frequency of administration (usually monthly), potentially serious side effects, and, most importantly, loss of efficacy with prolonged treatment. Gene transfer of endogenous antiangiogenic proteins is an alternative approach that has the potential to provide long-term suppression of neovascularization and/or excessive vascular leakage in the eye. Preclinical studies of gene transfer in a large animal model have provided impressive preliminary results with a number of transgenes. In addition, a clinical trial in patients suffering from advanced neovascular AMD has provided proof-of-concept for successful gene transfer. In this mini review, we summarize current theories pertaining to the application of gene therapy for neovascular AMD and the potential benefits when used in conjunction with endogenous antiangiogenic proteins.

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.

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.

PURPOSE: In between migraine attacks, some people show visual field defects that are worse when measured closer to the end of a migraine event. In this cohort study, we consider whether electrophysiological responses correlate with visual field performance at different times post-migraine, and explore evidence for cortical versus retinal origin. METHODS: Twenty-six non-headache controls and 17 people with migraine performed three types of perimetry (static, flicker and blue-on-yellow) to assess different aspects of visual function at two visits conducted at different durations post-migraine. On the same days, the pattern electroretinogram (PERG) and visual evoked response (PVER) were recorded. RESULTS: Migraine participants showed persistent, interictal, localised visual field loss, with greater deficits at the visit nearer to migraine offset. Spatial patterns of visual field defect consistent with retinal and cortical dysfunction were identified. The PERG was normal, whereas the PVER abnormality found did not change with time post-migraine and did not correlate with abnormal visual field performance. CONCLUSIONS: Dysfunction on clinical tests of vision is common in between migraine attacks; however, the nature of the defect varies between individuals and can change with time. People with migraine show markers of both retinal and/or cortical dysfunction. Abnormal visual field sensitivity does not predict abnormality on electrophysiological testing.

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.

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.

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.

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.

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.

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.

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.

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.

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.

PURPOSE: People with migraine often report aversion to flickering lights and show abnormal results on behavioural tasks that require the processing of temporal visual information. Studies have reported that the cortically evoked electrophysiological response to a flickering visual stimulus is abnormal; however, none have considered whether there is an underlying pre-cortical abnormality. In this cross-sectional study, we consider whether people with migraine have retinal and cortical electrophysiological abnormalities to flickering stimuli. METHODS: Monocular transient (1 Hz) and steady-state (8.3 Hz) pattern reversal electroretinograms (PERGs) and pattern visual evoked responses (PVERs) were measured simultaneously in 45 people with migraine (26 without aura, 19 with aura) and 30 non-headache controls at a time between migraine attacks. RESULTS: PERG amplitude and timing did not differ significantly between groups. Transient PVER amplitude was significantly reduced (28%) in the migraine with aura group compared to the controls F(2,72) = 3.6, p = 0.03). Both migraine groups showed significant reductions (32%, 39%) in steady-state PVER amplitude relative to controls (F(2,70) = 4.3, p = 0.02). CONCLUSIONS: This study finds normal retinal processing of flickering stimuli in the presence of abnormal cortical function between migraine attacks.

PURPOSE: The aim of this study was to investigate the relationship between clinical macular changes and retinal function in age-related macular degeneration (AMD). METHODS: We recruited 357 participants with visual acuity of better than 20/60 in the study eye, including 64 individuals with normal fundi and 293 AMD participants classified into 12 subgroups based upon the International Classification and Grading System. Visual function in the study eye was assessed using two steady-state tests (achromatic 14 Hz flicker [F14Hz] and isoluminant blue color [BCT]) and two adaptation measurements (cone photo-stress recovery rate [CRR] and rod dark adaptation recovery rate [RRR]). The groups were compared on their average psychophysical measurements and ranked according to functional deficiency. RESULTS: Both adaptation parameters were significantly abnormal when only hard and/or intermediate drusen were evident (compared to controls, P < 0.023) and yielded considerably worse outcomes in cases with more advanced fundus changes (P < 0.001), but provided limited ability to discriminate between these cases (linear trend, CRR t = 0.68, P = 0.50 and RRR t = 1.76, P = 0.08). Steady-state measurements, however, declined gradually along the entire hierarchy of fundus changes (linear trend, F14Hz t = 10.16, P < 0.001 and BCT t = 11.19, P < 0.001) with F14Hz being able to detect significant functional change as early as in the intermediate drusen group, when compared to controls (P = 0.003). CONCLUSIONS: Steady state thresholds (F14Hz and BCT) and clinical signs showed significant concordance across the spectrum of early AMD fundus changes. This suggests that these tests may be an effective tool for monitoring progression of AMD to supplement clinical grading.

Neuronal dysfunction has been noted very soon after the induction of diabetes by streptozotocin injection in rats. It is not clear from anatomical evidence whether glial cell dysfunction accompanies the well-documented neuronal deficit. Here, we isolate the Müller cell driven slow-P3 component of the full-field electroretinogram and show that it is attenuated at 4 weeks following the onset of streptozotocin-hyperglycaemia. We also found a concurrent reduction in the sensitivity of the phototransduction cascade, as well as in the components of the electroretinogram known to indicate retinal ganglion cell and amacrine cell integrity. Our data support the idea that neuronal and Müller cell dysfunction occurs at the same time in streptozotocin-induced hyperglycaemia.

PURPOSE: To examine retinal function using the full-field electroretinogram (ERG) during and after acute intraocular pressure (IOP) elevation in wild-type mice. METHODS: IOP was elevated by anterior chamber cannulation in wild-type C57/BL6 mice. The pressure-function relationship was determined by IOP elevation in steps from baseline to 80 mm Hg. The rate of functional recovery was assessed for 60 minutes after an IOP spike of 50 mm Hg for 30 minutes. During and immediately after IOP elevation, scotopic ERG signals were recorded in response to dim and bright flashes (-4.54, -2.23, and 0.34 log cd x s x m(-2)) and analyzed for photoreceptoral (a-wave), ON-bipolar (b-wave), oscillatory potentials (OPs), and scotopic threshold responses (positive [p]STR/negative [n] STR). A full ERG protocol was collected 2 days before and 7 days after the single 50-mm Hg IOP spike. RESULTS: The pSTR was most sensitive to IOP elevation with 50% amplitude loss (mu) at 41 mm Hg (mu, 95% confidence limits (CL): 37.7, 45.6) followed by nSTR at 45 mm Hg (95% CL: 41.0, 49.1). pSTR was significantly more sensitive than the b-wave (95% CL: 41.4, 49.1), a-wave (95% CL: 47.6, 55.3), and OPs (95% CL: 49.6, 59.2). pSTR showed slower recovery immediately after the 50 mm Hg spike compared with the b-wave (P = 0.02). One week after the 50-mm Hg spike, pSTR (-30% +/- 6%, P < 0.001) and OP (-27% +/- 2%, P < 0.001) amplitudes were reduced, whereas other components were unaffected. CONCLUSIONS: The STR in mice is more sensitive to acute IOP elevation and recovers slower than other ERG components. Reduction in pSTR and OP amplitude at 1 week suggests persistent impairment of inner retinal function can occur after a single IOP spike.