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Objective: To characterize functional and anatomic sequelae of a bleb induced by subretinal injection. Methods: Subretinal injections (100 μL) of balanced salt solution were placed in the superotemporal macula of 1 eye in 3 cynomolgus macaques. Fellow eyes received intravitreal injections (100 μL) of balanced salt solution. Fundus photography, ocular coherence tomography, and multifocal electroretinography were performed before and immediately after injection and again at intervals up to 3 months postinjection. Histopathologic analyses included transmission electron microscopy and immunohistochemistry for glial fibrillary acidic protein, rhodopsin, M/L-cone opsin, and S-cone opsin. Results: Retinas were reattached by 2 days postinjection (seen by ocular coherence tomography). Multifocal electroretinography waveforms were suppressed post- subretinal injection within the subretinal injection bleb and, surprisingly, also in regions far peripheral to this area. Multifocal electroretinography amplitudes were nearly completely recovered by 90 days. The spectraldomain ocular coherence tomography inner segment- outer segment line had decreased reflectivity at 92 days. Glial fibrillary acidic protein and S-cone opsin staining were unaffected. Rhodopsin and M/L-cone opsins were partially displaced into the inner segments. Transmission electron microscopy revealed disorganization of the outer segment rod (but not cone) discs. At all postinjection intervals, eyes with intravitreal injection were similar to baseline. Conclusions: Subretinal injection is a promising route for drug delivery to the eye. Three months post- subretinal injection, retinal function was nearly recovered, although reorganization of the outer segment rod disc remained disrupted. Understanding the functional and anatomic effects of subretinal injection is important for interpretation of the effects of compounds delivered to the subretinal space. [ABSTRACT FROM AUTHOR]

Purpose: Microcystoid macular degeneration (MMD) is a condition where cystoid vacuoles develop within the inner nuclear layer of the retina in humans in a variety of disorders. Here we report the occurrence of MMD in non-human primates (NHPs) with various retinal ganglion cell (RGC) pathologies and evaluate the hypothesis that MMD does not precede RGC loss but follows it., Methods: Morphological studies were performed of the retinas of NHPs, specifically both rhesus ( Macaca mulatta ) and cynomolgus macaques ( Macaca fascicularis ), in which MMD was identified after induction of experimental glaucoma (EG), hemiretinal endodiathermy axotomy (HEA), and spontaneous idiopathic bilateral optic atrophy. In vivo imaging analyses included fundus photography, fluorescein angiography (FA), optical coherence tomography (OCT), adaptive optics scanning laser ophthalmoscopy (AOSLO), light microscopy, and electron microscopy., Results: MMD, like that seen on OCT scans of humans, was found in both rhesus and cynomolgus macaques with EG. Of 13 cynomolgus macaques with chronic EG imaged once with OCT six of 13 animals were noted to have MMD. MMD was also evident in a cynomolgus macaque with bilateral optic atrophy. Following HEA, MMD did not develop until at least 2 weeks following the RNFL loss., Conclusion: These data suggest that MMD may be caused by a retrograde trans-synaptic process related to RGC loss. MMD is not associated with inflammation, nor would it be an independent indicator of drug toxicity per se in pre-clinical regulatory studies. Because of its inconsistent appearance and late development, MMD has limited use as a clinical biomarker.

Blue cone monochromacy (BCM) is a rare X-linked retinal disease characterized by the absence of L- and M-opsin in cone photoreceptors, considered a potential gene therapy candidate. However, most experimental ocular gene therapies utilize subretinal vector injection which would pose a risk to the fragile central retinal structure of BCM patients. Here we describe the use of ADVM-062, a vector optimized for cone-specific expression of human L-opsin and administered using a single intravitreal (IVT) injection. Pharmacological activity of ADVM-062 was established in gerbils, whose cone-rich retina naturally lacks L-opsin. A single IVT administration dose of ADVM-062 effectively transduced gerbil cone photoreceptors and produced a de novo response to long-wavelength stimuli. To identify potential first-in-human doses we evaluated ADVM-062 in non-human primates. Cone-specific expression of ADVM-062 in primates was confirmed using ADVM-062.myc, a vector engineered with the same regulatory elements as ADVM-062. Enumeration of human OPN1LW.myc-positive cones demonstrated that doses ≥3 × 10 10 vg/eye resulted in transduction of 18%-85% of foveal cones. A Good Laboratory Practice (GLP) toxicology study established that IVT administration of ADVM-062 was well tolerated at doses that could potentially achieve clinically meaningful effect, thus supporting the potential of ADVM-062 as a one-time IVT gene therapy for BCM., Competing Interests: Declaration of interests K.H., D.C., J.N., C.D., P.S., K.O.B., M.R., B.S., C.M.G., B.E.R., and R.N.G. are current or previous employees of Adverum Biotechnologies and hold stock grants. J.V.H. is a paid consultant of Adverum Biotechnologies., (Copyright © 2023 Adverum Biotechnologies Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: To determine whether short-latency changes in multifocal electroretinography (mfERG) observed in experimental glaucoma (EG) are secondary solely to retinal ganglion cell (RGC) loss or whether there is a separate contribution from elevated intraocular pressure (IOP)., Methods: Prior to operative procedures, a series of baseline mfERGs were recorded from six rhesus macaques using a 241-element unstretched stimulus. Animals then underwent hemiretinal endodiathermy axotomy (HEA) by placing burns along the inferior 180° of the optic nerve margin in the right eye (OD). mfERG recordings were obtained in each animal at regular intervals following for 3-4 months to allow stabilization of the HEA effects. Laser trabecular meshwork destruction (LTD) to elevate IOP was then performed; first-order kernel (K1) waveform root-mean-square (RMS) amplitudes for the short-latency segment of the mfERG wave (9-35 ms) were computed for two 7-hexagon groupings-the first located within the superior (non-axotomized) macula and the second within the inferior (axotomized) macula. Immunohistochemistry for glial fibrillary acidic protein (GFAP) was done., Results: By 3 months post HEA, there was marked thinning of the inferior nerve fiber layer as measured by optical coherence tomography. Compared with baseline, no statistically significant changes in 9-35 ms K1 RMS amplitudes were evident in either the axotomized or non-axotomized portions of the macula. Following LTD, mean IOP in HEA eyes rose to 46 ± 9 compared with 20 ± 2 mmHg (SD) in the fellow control eyes. In the HEA + EG eyes, statistically significant increases in K1 RMS amplitude were present in both the axotomized inferior and non-axotomized superior portions of the OD retinas. No changes in K1 RMS amplitude were found in the fellow control eyes from baseline to HEA epoch, but there was a smaller increase from baseline to HEA + EG. Upregulation of GFAP in the Müller cells was evident in both non-axotomized and axotomized retina in eyes with elevated IOP., Conclusions: The RMS amplitudes of the short-latency mfERG K1 waveforms are not altered following axotomy but undergo marked increases following elevated IOP. This suggests that the increase in mfERG amplitude was not solely a result of RGC loss and may reflect photoreceptor and bipolar cell dysfunction and/or changes in Müller cells., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: To evaluate sweep VEP (sVEP) in preverbal children with optic nerve hypoplasia (ONH) and to assess associations between sVEP results, patient clinical characteristics and future recognition visual acuity., Methods: The medical records of children with ONH who had sVEP testing and documented recognition visual acuity at the University of Wisconsin from 2005 to 2013 were reviewed retrospectively. Optic nerve size, amblyopia treatment, and neurologic diagnoses were collected., Results: A total of 57 patients were included: 41 (71%) with bilateral ONH and 27 (47%) with neurologic abnormality. Mean age at initial sVEP was 13.3 months (range, 1-32). Mean duration between initial sVEP and final recognition acuity was 5.5 years (range, 3.5-7). Sweep VEP was associated with ONH severity (P < 0.05). Sweep VEP, and the combination of ONH severity and neurologic status, were significant predictors (P < 0.05) of logMAR optotype acuity, together accounting for 54%-61% of the variance in final recognition acuity., Conclusions: Sweep VEP in preverbal children with ONH depends on ONH severity and correlates with final recognition visual acuity. Children with milder degrees of ONH without neurologic abnormalities had better final vision, and patients with severe ONH and neurologic diagnoses had worse vision outcomes., (Copyright © 2022 American Association for Pediatric Ophthalmology and Strabismus. Published by Elsevier Inc. All rights reserved.)

Purpose: We present 3 cases of Alström syndrome (ALMS) that highlight the importance of the ophthalmic exam, as well as the diagnostic challenges and management considerations of this ultra-rare disease., Observations: The first case is of a 2-year-old boy with history of spasmus nutans who presented with head bobbing and nystagmus. The second patient is a 5-year-old boy with history of infantile dilated cardiomyopathy status post heart transplant, Burkitt lymphoma status post chemotherapy, obesity, global developmental delay, and high hyperopia previously thought to have cortical visual impairment secondary to heart surgery/possible ischemic event. This patient presented with nystagmus, photophobia, and reduced vision. The third case involves a 8-year-old boy with history of obesity, bilateral optic nerve atrophy, hyperopic astigmatism, exotropia, and nystagmus. Upon presentation to the consulting pediatric ophthalmologist, none of the patients had yet been diagnosed with ALMS. All 3 cases were subsequently found to have an electroretinogram (ERG) that exhibited severe global depression and to carry ALMS1 pathogenic variants., Conclusions and Importance: ALMS is an autosomal recessive disease caused by ALMS1 variations, characterized by cone-rod dystrophy, obesity, progressive sensorineural hearing loss, cardiomyopathy, insulin resistance, and multiorgan dysfunction. Retinal dystrophy diagnosis is critical given clinical criteria and detection rates of genetic testing. Early diagnosis is extremely important because progression to flat ERG leads to the inability to differentiate between rod-cone or cone-rod involvement, either of which have their own differential diagnoses. In our series, the ophthalmic exam and abnormal ERG prompted further genetic testing and the subsequent diagnosis of ALMS. Multidisciplinary care ensures the best possible outcome with the ophthalmologist playing a key role., Competing Interests: We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome.The following authors have no financial disclosures: T.E., E.R.K., R.S., J.V·H., M.A.S., (© 2020 The Authors. Published by Elsevier Inc.)

Glaucoma, a multifactorial neurodegenerative disease characterized by progressive loss of retinal ganglion cells and their axons in the optic nerve, is a leading cause of irreversible vision loss. Intraocular pressure (IOP) is a risk factor for axonal damage, which initially occurs at the optic nerve head (ONH). Complex cellular and molecular mechanisms involved in the pathogenesis of glaucomatous optic neuropathy remain unclear. Here we define early molecular events in the ONH in an inherited large animal glaucoma model in which ONH structure resembles that of humans. Gene expression profiling of ONH tissues from rigorously phenotyped feline subjects with early-stage glaucoma and precisely age-matched controls was performed by RNA-sequencing (RNA-seq) analysis and complementary bioinformatic approaches applied to identify molecular processes and pathways of interest. Immunolabeling supported RNA-seq findings while providing cell-, region-, and disease stage-specific context in the ONH in situ. Transcriptomic evidence for cell proliferation and immune/inflammatory responses is identifiable in early glaucoma, soon after IOP elevation and prior to morphologically detectable axon loss, in this large animal model. In particular, proliferation of microglia and oligodendrocyte precursor cells is a prominent feature of early-stage, but not chronic, glaucoma. ONH microgliosis is a consistent hallmark in both early and chronic stages of glaucoma. Molecular pathways and cell type-specific responses strongly implicate toll-like receptor and NF-κB signaling in early glaucoma pathophysiology. The current study provides critical insights into molecular pathways, highly dependent on cell type and sub-region in the ONH even prior to irreversible axon degeneration in glaucoma.

Purpose: Vigabatrin (VGB) is an effective antiepileptic that increases concentrations of inhibitory γ-aminobutyric acid (GABA) by inhibiting GABA transaminase. Reports of VGB-associated visual field loss limit its clinical usefulness, and retinal toxicity studies in laboratory animals have yielded conflicting results., Methods: We examined the functional and morphologic effects of VGB in C57BL/6J mice that received either VGB or saline IP from 10 to 18 weeks of age. Retinal structure and function were assessed in vivo by optical coherence tomography (OCT), ERG, and optomotor response. After euthanasia, retinas were processed for immunohistochemistry, and retinal GABA, and VGB quantified by mass spectrometry., Results: No significant differences in visual acuity or total retinal thickness were identified between groups by optomotor response or optical coherence tomography, respectively. After 4 weeks of VGB treatment, ERG b-wave amplitude was enhanced, and amplitudes of oscillatory potentials were reduced. Dramatic rod and cone bipolar and horizontal cell remodeling, with extension of dendrites into the outer nuclear layer, was observed in retinas of VGB-treated mice. VGB treatment resulted in a mean 3.3-fold increase in retinal GABA concentration relative to controls and retinal VGB concentrations that were 20-fold greater than brain., Conclusions: No evidence of significant retinal thinning or ERG a- or b-wave deficits were apparent, although we describe significant alterations in ERG b-wave and oscillatory potentials and in retinal cell morphology in VGB-treated C57BL/6J mice. The dramatic concentration of VGB in retina relative to the target tissue (brain), with a corresponding increase in retinal GABA, offers insight into the pathophysiology of VGB-associated visual field loss.

Multiple sclerosis (MS) is a common cause of neurologic disease in young adults that is primarily treated with disease-modifying therapies which target the immune and inflammatory responses. Promotion of remyelination has opened a new therapeutic avenue, but how best to determine efficacy of remyelinating drugs remains unresolved. Although prolongation and then shortening of visual evoked potential (VEP) latencies in optic neuritis in MS may identify demyelination and remyelination, this has not been directly confirmed. We recorded VEPs in a model in which there is complete demyelination of the optic nerve, with subsequent remyelination. We examined the optic nerves microscopically during active disease and recovery, and quantitated both demyelination and remyelination along the length of the nerves. Latencies of the main positive component of the control VEP demonstrated around 2-fold prolongation during active disease. VEP waveforms were nonrecordable in a few subjects or exhibited a broadened profile which precluded peak identification. As animals recovered neurologically, the VEP latencies decreased in association with complete remyelination of the optic nerve but remained prolonged relative to controls. Thus, it has been directly confirmed that VEP latencies reflect the myelin status of the optic nerve and will provide a surrogate marker in future remyelination clinical trials.

Laser-induced experimental glaucoma (ExGl) in non-human primates (NHPs) is a common animal model for ocular drug development. While many features of human hypertensive glaucoma are replicated in this model, structural and functional changes in the unlasered portions of trabecular meshwork (TM) of laser-treated primate eyes are understudied. We studied NHPs with ExGl of several years duration. As expected, ExGl eyes exhibited selective reductions of the retinal nerve fiber layer that correlate with electrophysiologic measures documenting a link between morphologic and elctrophysiologic endpoints. Softening of unlasered TM in ExGl eyes compared to untreated controls was observed. The degree of TM softening was consistent, regardless of pre-mortem clinical findings including severity of IOP elevation, retinal nerve fiber layer thinning, or electrodiagnostic findings. Importantly, this softening is contrary to TM stiffening reported in glaucomatous human eyes. Furthermore, microscopic analysis of unlasered TM from eyes with ExGl demonstrated TM thinning with collapse of Schlemm's canal; and proteomic analysis confirmed downregulation of metabolic and structural proteins. These data demonstrate unexpected and compensatory changes involving the TM in the NHP model of ExGl. The data suggest that compensatory mechanisms exist in normal animals and respond to elevated IOP through softening of the meshwork to increase outflow.

Applied Genetic Technologies Corporation (AGTC) is developing rAAV2tYF-PR1.7-hCNGB3, a recombinant adeno-associated virus (rAAV) vector expressing the human CNGB3 gene, for treatment of achromatopsia, an inherited retinal disorder characterized by markedly reduced visual acuity, extreme light sensitivity, and absence of color discrimination. We report here results of a study evaluating safety and biodistribution of rAAV2tYF-PR1.7-hCNGB3 in CNGB3-deficient mice. Three groups of animals (n = 35 males and 35 females per group) received a subretinal injection in one eye of 1 μl containing either vehicle or rAAV2tYF-PR1.7-hCNGB3 at one of two dose concentrations (1 × 10(12) or 4.2 × 10(12) vg/ml) and were euthanized 4 or 13 weeks later. There were no test-article-related changes in clinical observations, body weights, food consumption, ocular examinations, clinical pathology parameters, organ weights, or macroscopic observations at necropsy. Cone-mediated electroretinography (ERG) responses were detected after vector administration in the treated eyes in 90% of animals in the higher dose group and 31% of animals in the lower dose group. Rod-mediated ERG responses were reduced in the treated eye for all groups, with the greatest reduction in males given the higher dose of vector, but returned to normal by the end of the study. Microscopic pathology results demonstrated minimal mononuclear cell infiltrates in the retina and vitreous of some animals at the interim euthanasia and in the vitreous of some animals at the terminal euthanasia. Serum anti-AAV antibodies developed in most vector-injected animals. No animals developed antibodies to hCNGB3. Biodistribution studies demonstrated high levels of vector DNA in vector-injected eyes but little or no vector DNA in nonocular tissue. These results support the use of rAAV2tYF-PR1.7-hCNGB3 in clinical studies in patients with achromatopsia caused by CNGB3 mutations.

Applied Genetic Technologies Corporation (AGTC) is developing rAAV2tYF-PR1.7-hCNGB3, a recombinant adeno-associated viral (rAAV) vector expressing the human CNGB3 gene, for treatment of achromatopsia, an inherited retinal disorder characterized by markedly reduced visual acuity, extreme light sensitivity, and absence of color discrimination. We report here results of a study evaluating the safety and biodistribution of rAAV2tYF-PR1.7-hCNGB3 in cynomolgus macaques. Three groups of animals (n = 2 males and 2 females per group) received a subretinal injection in one eye of 300 μl containing either vehicle or rAAV2tYF-PR1.7-hCNGB3 at one of two concentrations (4 × 10(11) or 4 × 10(12) vector genomes/ml) and were evaluated over a 3-month period before being euthanized. Administration of rAAV2tYF-PR1.7-hCNGB3 was associated with a dose-related anterior and posterior segment inflammatory response that was greater than that observed in eyes injected with the vehicle control. Most manifestations of inflammation improved over time except that vitreous cells persisted in vector-treated eyes until the end of the study. One animal in the lower vector dose group was euthanized on study day 5, based on a clinical diagnosis of endophthalmitis. There were no test article-related effects on intraocular pressure, visual evoked potential responses, hematology or clinical chemistry parameters, or gross necropsy observations. Histopathological examination demonstrated minimal mononuclear infiltrates in all vector-injected eyes. Serum anti-AAV antibodies developed in all vector-injected animals. No animals developed antibodies to CNGB3. Biodistribution studies demonstrated high levels of vector DNA in the injected eye but minimal or no vector DNA in any other tissue. These results support the use of rAAV2tYF-PR1.7-hCNGB3 in clinical studies in patients with achromatopsia caused by CNGB3 mutations.

Applied Genetic Technologies Corporation is developing rAAV2tYF-CB-hRS1, a recombinant adeno-associated virus (rAAV) vector for treatment of X-linked retinoschisis (XLRS), an inherited retinal disease characterized by splitting (schisis) of retinal layers causing poor vision. We report here results of a study evaluating the safety and biodistribution of rAAV2tYF-CB-hRS1 in normal cynomolgus macaques. Three groups of male animals (n = 6 per group) received an intravitreal injection in one eye of either vehicle, or rAAV2tYF-CB-hRS1 at one of two dose levels (4 × 10(10) or 4 × 10(11) vg/eye). Half the animals were sacrificed after 14 days and the others after 91 or 115 days. The intravitreal injection procedure was well tolerated in all groups. Serial ophthalmic examinations demonstrated a dose-related anterior and posterior segment inflammatory response that improved over time. There were no test article-related effects on intraocular pressure, electroretinography, visual evoked potential, hematology, coagulation, clinical chemistry, or gross necropsy observations. Histopathological examination demonstrated minimal or moderate mononuclear infiltrates in 6 of 12 vector-injected eyes. Immunohistochemical staining showed RS1 labeling of the ganglion cell layer at the foveal slope in vector-injected eyes at both dose levels. Serum anti-AAV antibodies were detected in 4 of 6 vector-injected animals at the day 15 sacrifice and all vector-injected animals at later time points. No animals developed antibodies to RS1. Biodistribution studies demonstrated high levels of vector DNA in the injected eye but minimal or no vector DNA in any other tissue. These results support the use of rAAV2tYF-CB-hRS1 in clinical studies in patients with XLRS.

Purpose: Systemic neoplastic processes can affect the retina through autoimmune retinopathy. This process may present in a variety of patterns. A novel pattern of paraneoplastic autoimmune retinopathy has been described., Methods: Two patients presented with paraneoplastic vision changes. Optical coherence tomography and multifocal electroretinography were performed, which showed a unique focal retinal change in both patients. Case 1 is a 20-year-old woman with history of cutaneous melanoma. Case 2 is 67-year-old woman with history of breast cancer., Results: Both patients showed a localized area of foveal thinning that corresponded with areas of depression on multifocal electroretinography. Each tested positive for antiretinal antibodies., Conclusion: This is a novel manifestation of paraneoplastic autoimmune retinopathy. Previously described cases have all affected the retina diffusely. These cases highlight the need to consider distant neoplastic processes when evaluating patient with similar presentations to those depicted here.

The development path described for JNJ-26489112 provides perspectives on interpretation of retinal effects observed in nonclinical studies and their implications for clinical development. JNJ-26489112 is a CNS-active investigational drug that has potential as a novel treatment for treatment-resistant and bipolar depression, epilepsy, and neuropathic/inflammatory pain. In a 6-month toxicity study in albino rats, retinal atrophy was observed at supratherapeutic exposures to JNJ-26489112. The histopathological changes and topography of the lesions were characteristic of light-induced damage specific to albino rats. The species/strain specificity is supported by an absence of any ocular effects in dogs and in pigmented and albino rats, housed under standard and reduced lighting, respectively. To further evaluate its potential to cause ocular effects, in vivo functional and structural ocular analyses were included in a 9-month monkey toxicity study. Reductions in rod- and cone-mediated electroretinograms were observed at supratherapeutic exposures but without any histopathologic changes. These data suggested that the effects of JNJ-26489112 in monkeys were neuromodulatory and not neurotoxic. Taken together, data related to the light-induced atrophy in albino rats and reversible neuromodulatory effects in monkeys, supported the safe evaluation of JNJ-26489112 in a clinical proof-of-concept study that included comprehensive functional and structural ocular monitoring., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Purpose: Outer retinal injury has been well described in glaucoma. To better understand the source of this injury, we wanted to develop a reliable model of partial retinal ganglion cell (RGC) axotomy., Methods: Endodiathermy spots were placed along the inferior 180° adjacent to the optic nerve margin in the right eyes of four cynomolgus monkeys. Fluorescein angiography, spectral domain optical coherence tomography (SD-OCT), and multifocal electroretinography (mfERG) were performed at various intervals. Two animals were sacrificed at 3 months. Two animals were sacrificed at 4 months, at which time they underwent an injection of fluorescent microspheres to measure regional choroidal blood flow. Retinal immunohistochemistry for glial fibrillary acidic protein (GFAP), rhodopsin, S-cone opsin, and M/L-cone opsin were performed, as were axon counts of the optic nerves., Results: At 3 months, there was marked thinning of the inferior nerve fiber layer on SD-OCT. The mfERG waveforms were consistent with inner but not outer retinal injury. Greater than 95% reduction in axons was seen in the inferior optic nerves but no secondary degeneration superiorly. There was marked thinning of the nerve fiber and ganglion cell layers in the inferior retinas. However, the photoreceptor histology was similar in the axotomized and nonaxotomized areas. Regional choroidal blood flow was not affected by the axotomy., Conclusions: Unlike experimental glaucoma, hemiretinal endodiathermy axotomy (HEA) of the RGCs produces no apparent anatomic, functional, or blood flow effects on the outer retina and choroid.

We report a focal disturbance in myelination of the optic nerve in the osteopetrotic (op/op) mouse, which results from a spontaneous compression of the nerve resulting from stenosis of the optic canal. The growth of the op/op optic nerve was significantly affected, being maximally suppressed at postnatal day 30 (P30; 33% of age matched control). Myelination of the nerve in the optic canal was significantly delayed at P15, and myelin was almost completely absent at P30. The size of nerves and myelination were conserved both in the intracranial and intraorbital segments at P30, suggesting that the axons in the compressed site are spared in all animals at P30. Interestingly, we observed recovery both in the nerve size and the density of myelinated axons at 7 months in almost half of the optic nerves examined, although some nerves lost axons and became atrophic. In vivo and ex vivo electrophysiological examinations of P30 op/op mice showed that nerve conduction was significantly delayed but not blocked with partial recovery in some mice by 7 months. Transcardial perfusion of FITC-labeled albumin suggested that local ischemia was at least in part the cause of this myelination failure. These results suggest that the primary abnormality is dysmyelination of the optic nerve in early development. This noninvasive model system will be a valuable tool to study the effects of nerve compression on the function and survival of oligodendrocyte progenitor cells/oligodendrocytes and axons and to explore the mechanism of redistribution of oligodendrocyte progenitor cells with compensatory myelination.

Purpose. The scanning laser polarimetry with variable corneal compensation (GDx VCC) methodology was established and verified in monkeys with experimental glaucoma (ExpG). Terminal GDx parameters were correlated with axon counts and electrophysiologic measures. The effects of memantine on these parameters were investigated. Methods. ExpG was induced in monkeys and intraocular pressure monitored weekly. Some monkeys received memantine in their diet before and after ExpG induction (1-10 months). GDx VCC scans, stereophotographs, and multifocal visual evoked potential (mfVEP) data were collected at baseline and every 6 to 8 weeks until euthanasia. Optic nerves were prepared for axon counting and other morphologic analysis. Results. There was no difference in IOP elevation exposure between memantine-treated and no-memantine-treated monkeys. The percentage of the optic nerve area composed of connective tissue septa was significantly greater in ExpG eyes than in Fellow eyes. There was a strong positive correlation between axon counts and terminal GDx parameter measures. Animals not receiving memantine exhibited significantly lower mfVEP amplitudes in ExpG eyes compared with the ipsilateral baseline or the final value in the Fellow eye. ExpG eyes from memantine-treated animals had higher overall mean amplitudes that were not significantly different relative to the ipsilateral baseline and final amplitudes in the Fellow eye. Conclusions. The authors' studies confirm that GDx VCC can be utilized in monkey ExpG studies to detect early retinal structural changes and that these changes are highly correlated with optic nerve axon counts. These structural changes may or may not lead to central functional changes as shown by the mfVEP in response to investigational therapies.

We compared the suitability of pentobarbital sodium (PB) and propofol (PF) anesthetics for multifocal electroretinograms (mfERGs) in rhesus macaques. mfERGs were collected from 4 ocularly normal rhesus macaques. All animals were pre-anesthetized with intramuscular ketamine (10-15 mg/kg). Intravenous PB induction/maintenance levels were 15 mg/kg/2-10 mg/kg and for PF, 2-5 mg/kg/6-24 mg/kg/h. There were 3 testing sessions with PB anesthesia and 5-7 testing sessions with PF anesthesia. All PB sessions were carried out before PF. First-order (K1) and second-order (first slice) kernels (K2.1) response density amplitude (RDA), implicit time (IT), and root mean square signal-to-noise ratios (RMS SNR) of the low-frequency (LFC) and high-frequency (HFC) components were evaluated. The use of PF or PB anesthesia resulted in robust, replicable mfERGs in rhesus macaques; however, RMS SNR of K1 LFC in ring and quadrant analyses was significantly larger for PF than for PB. Additionally, K1 RDA under PF was significantly larger than under PB for N1, P1, and P2 components (ring and quadrant) and for N2 (quadrant). PF IT was significantly prolonged (<1 ms) relative to PB IT for N1, P1 (ring), and N1 (quadrant), while PB IT was significantly prolonged (0.8-4.2 ms) relative to PF IT for N2 and P2 (ring and quadrant). K1 HFC and K2.1 LFC did not differ significantly between PB and PF in the ring or quadrant analyses. The response differences found with PB and PF anesthesia likely arise from variable relative effects of the anesthetics on retinal γ-aminobutyric acid (GABA(A)) receptors, and in part, on glycine and on glutamate receptors. Given the advantages of a stable anesthetic plane with continuous intravenous infusion and a smoother, more rapid recovery, PF is an appealing alternative for mfERG testing in rhesus macaques.

The purpose of this study was to evaluate the relationship between elevations of intraocular pressure (IOP) and the multifocal electroretinogram (mfERG) in non-human primates. Experimental glaucoma was induced in 4 rhesus and 4 cynomolgus monkeys by laser trabecular meshwork destruction (LTD) in one eye. To evaluate the contribution of ganglion cells to mfERG changes, one monkey of each species had previously underwent unilateral optic nerve transection (ONT). After >or=44 weeks of elevation, the IOP was reduced by trabeculectomy in 2 non-transected animals. In the intact (non-transected) animals, there was an increase in the amplitude of the early mfERG waveforms (N1 and P1) of the first-order kernel (K1) throughout the period of IOP elevation in all of the rhesus, but not all of the cynomolgus monkeys. A species difference was also present as a decrease of the second-order kernel, first slice (K2.1) in all of the cynomolgus monkeys but only in 1 of the rhesus monkeys (the 1 with the ONT). Similar IOP effects on the mfERG were seen in the ONT animals. Surgical lowering of IOP resulted in a return of the elevated K1 amplitudes to baseline levels. However, the depressed K2.1 RMS in the cynomolgus monkeys did not recover. These results demonstrate species-specific changes in cone-driven retinal function during periods of elevated IOP. These IOP-related effects can occur in the absence of retinal ganglion cells and may be reversible.

Purpose: The objective of this study was to perform a preliminary evaluation of the ocular and systemic safety of calcium formate, a dietary calcium supplement for prevention and management of osteoporosis. Although formate is an endogenous product of metabolism, high concentrations are associated with toxicity during methanol overdose., Methods: In this prospective clinical trial, 12 healthy women ingested calcium formate (1,300 mg) three times a day for 14 days. Study evaluations included physical and ocular examination, extensive laboratory testing, serum calcium and formate levels, Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity, color vision, visual fields, visual evoked potential (VEP), and full-field, pattern, and multifocal electroretinograms (MERG)., Results: The mean baseline serum level of formate was 0.572 +/- 0.06 mM. Peak serum levels and final serum formate did not differ significantly from baseline. The final concentration was 0.582 +/- 0.091 mM. Accumulation of serum formate did not occur. There was also no evidence of toxicity with calcium formate ingestion. All examinations and tests remained normal, including optic nerve and retinal function. Three subjects had mild transient symptoms attributable to any calcium formulation., Conclusions: Calcium formate is highly bioavailable and well-tolerated. Serum formate remained at basal levels and did not accumulate with repeated dosing. Systemic and ocular safety was demonstrated by objective testing. Given its high oral bioavailability, calcium formate may be a good choice for calcium supplementation in the prevention and management of osteoporosis. Further study will be needed to evaluate its long-term safety in a larger group of subjects representing more varied age, health, dietary, and nutritional status.

Recent reports from large clinical trials have clearly demonstrated that lowering intraocular pressure (IOP) in persons with ocular hypertension has a beneficial effect on reducing the progression of glaucomatous disease. Few studies of this effect have been conducted in controlled laboratory settings, however, none have been conducted using non-human primates, the model of experimental glaucoma considered most similar to the human disease. Using data collected retrospectively from a trabeculectomy study using 16 cynomolgous monkeys with experimental ocular hypertension, we evaluated both the threshold of elevated IOP required to cause clinically observable damage to the optic nerve head and also if lowering IOP below this threshold prevents further damage. An index of the level of elevated IOP experienced by experimental eyes (the Pressure Insult) was calculated as the slope of the difference in cumulative IOP between experimental and control eyes during four intervals of time over the course of the experiment, while damage to the optic nerve head was evaluated by measuring the Cup:Disc ratio for each eye from stereoscopic photographs taken at the end of each interval. An increase in the Cup:Disc ratio was significantly associated with both the maximum IOP obtained in the experimental eye during each interval (r=0.573, P<0.001) and the Pressure Insult (r=0.496, P<0.001). Pressure Insult values less than 11 mm Hg Days/Day were not associated with glaucomatous damage in monkey eyes, whereas values greater than 11 showed a significant correlation with increasing Cup:Disc ratios (P<0.001). Trabeculectomy to reduce the Pressure Insult below 11 was correlated with an attenuation of the rate of progression of the Cup:Disc ratio in eyes that had exhibited damage before surgery. These results contribute further to our understanding of this model of experimental glaucoma by demonstrating a threshold at which IOP needs to be elevated to stimulate damage, while also providing corroborating evidence that lowering IOP in ocular hypertensive monkeys can attenuate the progression of glaucomatous disease.

Purpose: To evaluate monkey multifocal visual evoked cortical potentials (mfVEPs) recorded from central and peripheral fields for reliability and isolation from electroretinographic (ERG) activity., Methods: The mfVEP stimulus consisted of a 7-element hexagonal array that subtended 80 degrees of the central visual field. Recordings were made under intravenous pentobarbital sodium (15 mg/kg) anesthesia. Two monkeys with absent optic nerve and ganglion cell function after combined unilateral optic nerve transection and experimental ocular hypertension (ONT/OHT) were followed longitudinally. In a second study, 16 ophthalmologically normal monkeys were tested once., Results: Testing of the non-transected eye in two transected animals revealed robust first- and second-order kernel, first slice (K1 and K2.1) mfVEPs. Stimulation of the transected eye revealed no contamination of the mfVEP from the concurrently recorded multifocal ERGs. There was complete separation of the root-mean-square (RMS) mfVEP amplitudes from the transected and the fellow eyes tested repeatedly across a 4- to 17- month period. The largest amplitude mfVEP was generated by the central element; however, mfVEPs were recorded from outside the central 20 degrees element. The 16 normal animals showed waveforms similar to the normal eyes of the ONT/OHT animals both in shape and distribution throughout the visual field. A scalar-product measure showed both K1 and K2.1 mfVEPs from central and some peripheral elements were statistically distinct from noise., Conclusions: mfVEPs can be reliably recorded from non-human primates anesthetized with pentobarbital. Under the recording conditions described, mfVEPs are not contaminated by ERG activity. mfVEPs may be useful in animal models of diseases that differentially affect macular and peripheral visual field responsiveness.

Objective: To develop a quantitative measure of regional variation in choroidal blood flow (ChBF)., Methods: Five million 15-microm fluorescent microspheres were injected into the left ventricles of 4 rabbits and 3 monkeys. The fixed globes were bleached, flat mounted, and photomicrographed. After image analysis to locate each microsphere, regional densities and blood flow were determined., Results: Regional variation in ChBF was clearly evident. In the rabbit, a high density of spheres was seen in the visual streak. This was surrounded by a middle peripheral area of low sphere density and a far peripheral region of moderately high density. In the monkeys, sphere density was markedly greater in the macula compared with the periphery. Contour plots produced lines of constant flow that were oval and extended farther nasally than temporally in the monkeys. The ratio of central to peripheral ChBF was much greater in the monkeys than in the rabbits., Conclusion: Quantitative assessment of regional ChBF can be performed using a modification of the fluorescent microsphere impaction method., Clinical Relevance: This method of determining regional ChBF will be useful for studying the vascular effects of pharmacologic agents and for characterizing animal models of human disease involving the outer retina.

Purpose: To investigate the effects of H-7 and Latrunculin B (Lat-B) on retinal vascular permeability and electrophysiology at concentrations that increase outflow facility in monkeys., Methods: One eye of 1 rhesus and 22 cynomolgus monkeys received an intravitreal bolus injection of H-7 or Lat-B; the opposite eye received vehicle. Multifocal electroretinograms (mfERGs), and photopic and scotopic full-field electroretinograms (ffERGs, sERGs) were recorded in subsets of monkeys at baseline and at multiple time-points post-H-7 or Lat-B. Vitreous fluorophotometry (VF) and fluorescein angiography (FA) were also performed., Results: No differences between the H-7 or Lat-B treated and control eyes were found in ffERGs, mfERGs, sERGs, or in FAs in any monkey. No significant difference was found in vitreous fluorescein levels between H-7 treated or Lat-B treated vs. control eyes., Conclusions: No effect on retinal vascular permeability or retinal electrophysiology was apparent after intravitreal administration of H-7 or Lat-B at doses that increase outflow facility and lower IOP when given intracamerally.

The purpose of this study is to ascertain whether inherent differences exist in the retinal function of two macaque species that are commonly used in experimental glaucoma investigations. We quantified and compared multifocal electroretinograms (mfERGs) from ocularly normal cynomolgus (n = 36) and rhesus (n = 18) monkeys. The stimulus array consisted of 103 equal-sized hexagonal elements, which subtended +/-44 degrees about the central visual axis. Mean luminance of the display was 100 cd/m2. The firstorder kernel (K1) and second-order (first slice) kernel (K2) of the mfERG were averaged into 4 rings radiating from the foveal element, and represented the central 56 degrees of visual field. Fifteen and 30-element segments were used for K1 and K2 quadrant and hemiretinal response determinations, respectively. Response measures for the rings, quadrants, and hemiretinae included K1 amplitude and implicit time, and K1 and K2 oscillatory potentials (OPs) and response amplitude root mean square (RMS). Species, gender, and retinotopic differences were assessed with repeated measures analysis of variance (split plot design). K1 amplitudes of the N1 waves, K1 and K2 OPs and K2 amplitude RMS for the ring, quadrant, and hemiretinal mfERG waveforms were larger in rhesus than in cynomolgus monkeys. Rhesus males (as compared to rhesus females) and cynomolgus females (as compared to cynomolgus males) exhibited larger amplitudes and less delayed implicit times in the central retina. These results demonstrate that species-specific differences in retinal function are evident in cynomolgus and rhesus monkeys. There also were gender-associated differences that varied across species. Thus, investigators should exercise caution when data from species or gender are combined.

Objective: To determine whether selective cone loss could explain the acquired tritan-like color confusion found in diabetic retinopathy., Methods: Terminal deoxynucleotidyl transferase-mediated biotin-deoxyuridine triphosphate nick end labeling (TUNEL) was employed on paraffin sections of retinas from 5 donors with diabetic retinopathy. For quantitative analysis, postmortem retinas were obtained from 13 human donors; 7 from patients with various durations and stages of diabetic retinopathy (4 background, 3 proliferative) and 6 controls. Enzyme histochemical analysis for carbonic anhydrase (CA) was used to distinguish L/M-cones (positive for CA) from S-cones (negative for CA). Cone topography was determined by sampling 360 degrees from 0.1 to 1.5 mm of foveal eccentricity and along the horizontal meridians from 1.5 to 15.0 mm., Results: Rare cells in both the inner and outer nuclear layers of the diabetic eyes were positively labeled with the TUNEL method. The CA staining revealed incomplete and patchy losses of S-cones that were limited to the diabetic retinas. Statistically significant reduction in the density of S-cones was found at nearly all foveal eccentricities from 0.1 mm to 15.0 mm. This was not the case for the L/M-cones. On average, for all locations, the percentage of S-cones compared with L/M-cones was decreased by 21.0% +/- 3.4% with respect to the controls., Conclusion: The S-cones selectively die in diabetic retinopathy., Clinical Relevance: Selective loss of S-cones may contribute to the tritan-like color vision deficit seen in patients with diabetic retinopathy.

Objective: To test a hypothesis of photoreceptor involvement in retinal ganglion cell (RGC) death in chronic glaucoma., Methods: Laser spots were applied to 6 eyes of 3 rhesus monkeys, causing focal destruction of the outer retina, including the photoreceptors. After 3 to 4 weeks, experimental glaucoma was induced in the right eyes of each monkey using argon laser trabecular destruction (ALTD). The intraocular pressures in these eyes were elevated for 3 to 7 months. As a control, 1 additional monkey underwent retinal laser photocoagulation followed by optic nerve transection instead of ALTD. Following enucleation, the retinas were embedded and sectioned for histologic evaluation., Results: There was extensive loss of RGCs in the eyes with ALTD except over the large retinal laser spots, where there was an increased survival of RGCs. The RGC protection was not observed in the monkey that had undergone optic nerve transection., Conclusion: Photocoagulation of the outer retina that completely destroys the photoreceptors results in survival of the overlying RGCs in experimental glaucoma in monkey eyes., Clinical Relevance: Although this is an experimental model and not a therapeutic option, these results suggest that treatments other than lowering intraocular pressure may be potential therapies for preventing RGC death in glaucomatous eyes. Arch Ophthalmol. 2000;118:1242-1250

Objective: To determine whether outer retinal changes occur in chronic, presumed primary open-angle glaucoma (POAG)., Methods: The outer retinas from 128 human eyes with a diagnosis of chronic glaucoma (presumably POAG in most cases) and 90 control eyes were examined histologically by 3 masked observers for photoreceptor swelling and loss. Retinas from 9 rhesus monkeys with glaucoma induced experimentally by laser trabecular destruction were compared with 7 fellow (control) eyes. The mean pressure elevations in the eyes with laser trabecular destruction ranged from 26.6 to 53.6 mm Hg with durations varying from 7 to 33 weeks., Results: Swelling of the red- and green-sensitive cones was observed in a statistically significantly greater proportion of human eyes with presumed POAG compared with the control eyes. Patchy loss of red/green cones and rods was also found in some of the glaucomatous retinas. In a subset of the human eyes with end-stage disease, cone swelling was a variable finding. Although no photoreceptor loss was found in the 9 monkey eyes with experimental glaucoma, 8 had swelling of their red/green cones that was remarkably similar to that seen in the human eyes. Swelling was not present in any of the control monkey eyes., Conclusions: The photoreceptors are affected by chronically elevated intraocular pressure., Clinical Relevance: These findings may explain some of the abnormalities of color vision and the electrophysiological effects that have been observed in patients with POAG.

This study used the swept spatial-frequency method to compare retinal and cortical acuity in anesthetized young adult rhesus monkeys. Visual evoked potentials (VEPs) and pattern electroretinographic responses (PERGs) were recorded from 25 monkeys (age range: 4-12 years) anesthetized with a continuous infusion of propofol. The stimuli were temporally countermodulated sine-wave gratings that increased in spatial frequency within a 10.24-s period. All animals were refracted using acuity estimated from the zero micro-volt intercept of the linear regression of evoked potential amplitude on spatial frequency. Average sweep acuities were 23.7 cycles/deg +/- 1.5 S.E.M. and 23.1 cycles/deg +/- 1.8 S.E.M. for the PERG and VEP, respectively. VEP and PERG acuities were within the range expected based on acuities estimated from behavioral studies in macaques. PERG and VEP acuities were highly correlated (r = 0.90) and equally sensitive to spherical blur. On a subset of animals, test-retest reliability of animals, and interocular correlations, were high (r = 0.87 and r = 0.83, respectively). Increasing propofol dosage 8-fold did not degrade PERG or VEP acuity. This study demonstrates that high spatial-frequency acuities can be rapidly obtained from young adult rhesus monkeys under a wide dose range of propofol anesthesia using the swept spatial-frequency method.

Purpose: The validity of retinoscopy in small eyes has not been clearly established due to uncertainty regarding the source of the ocular reflections assessed during this procedure. A widely cited model which proposes that their origin is the inner limiting membrane of the retina was evaluated in the rat by comparing refractive errors measured by retinoscopy to those measured by visual evoked potentials (VEPs)., Methods: Ten rats were refracted both by cycloplegic streak retinoscopy and by VEP while viewing 0.05 to 0.15 cpd square-wave gratings-reversed at 1.875 Hz. Spherical aberration of the rat eye was assessed as a potentially confounding variable in VEP refraction by sequential retinoscopic refractions across the rat's natural pupil through a 1.5-mm pinhole., Results: All animals were moderately to highly hyperopic by both methods (range = +4.5 to +18.5 D). Spherical aberration was minimal (median = 3.5 D of overcorrected aberration). The median difference between retinoscopic refractions and those by VEP was not significant (+1.94 D more hyperopia by retinoscopy; p = 0.062, Wilcoxon signed rank) but was significantly less than the +9.64 D difference predicted by an inner limiting membrane model (upper 95% limit = +3.76 D)., Conclusion: This suggests that the origin of the retinoscopic reflex is located in the outer retina rather than at the inner limiting membrane. Correction factors for retinoscopy in small eyes may be smaller than previously assumed.

This study examines the relationship between clinically assessed binocular sensory status and binocular visual evoked potentials (BVEPs) in 11 patients with monofixation syndrome (MFS) and in 12 patients with absent binocular fusion (ABF). BVEPs were elicited using a two-sinusoid "beat" technique. The luminances of red/green anaglyphic circular fields were modulated independently at temporal rates of 6 and 8 Hz. This stimulus elicits a BVEP at 14 Hz in children with normal stereoscopic vision. In this study, we found that this BVEP also is present in patients with MFS, whereas it is near background noise levels in patients with ABF. These results demonstrate the presence of functional binocular cortical mechanisms in patients with MFS. The findings are consistent with the hypothesis that elicitation of this class of BVEPs requires gross sensory fusion, but not fine stereoscopic vision.

Purpose: Color vision testing in young children typically is precluded by the motor and cognitive skills required by standard tests; yet this information can be useful for diagnosis and counseling in many conditions. The purpose of this study is to evaluate a visual evoked potential (VEP) method for assessing red-green color vision anomalies in pediatric patients., Method: The relative chromatic luminance (C = R/R + G) of a rapidly reversing red-green checkerboard was varied across a wide range within a short viewing period (10 sec). Swept-parameter VEP methods were used to measure the cortical response to the range of C presented., Results: Individuals with normal color vision exhibit a VEP response that exceeds noise levels across all values of C, often with an amplitude minima near the photopic equiluminant point (C = 0.5). Results from children with established protan and deutan color vision anomalies show loss of VEP amplitude and phase at values of C consistent with the respective color defect. A patient with achromatopsia showed a generalized depression of VEP response across all values of C tested., Conclusion: Color sweep VEP techniques appear promising for the clinical assessment of color status in pediatric patients.

Since commonly used clinical methods of measuring binocular function require subjective responses, this testing has been limited to more cooperative children, usually older than 2 years of age. Recently, we have begun using a clinically practical, visually evoked cortical potential (VECP) method to detect the presence of binocular neurons in infants and young children. We studied 14 children, ages 4 to 44 months, with infantile esotropia. Nine had surgical correction for esotropia by the age of 2 years. Twenty-five normal infants ages 6 weeks to 22 months served as controls. Most normal infants showed the development of the "beat" by 2 months of age. The "sum" VECP was not consistently present until age 6 months. Four of the five esotropic infants less than 1 year of age, demonstrated neither a "sum" nor "beat" response. All nine patients with corrective surgery performed before 2 years of age developed a significant sum response and three developed a beat. Five patients had not had surgery until after 2 years of age. Two developed a sum and one a beat, but none had both beat and sum responses. The results suggest that there is a loss of nonlinear binocular response in esotropic children not corrected before the age of 2 years and that these responses can be restored after early treatment even if not present at the time of surgery.

Spatiotemporal contrast sensitivity at three orientations, vertical, horizontal and oblique, was studied in 18 patients with clinically definite and laboratory-confirmed definite multiple sclerosis (MS). Nineteen age-matched control subjects were also studied under identical experimental conditions. Contrast thresholds for detecting steady and counterphase modulated (5 Hz) gratings ranging in spatial frequency from 0.5 to 12 c/deg were measured by a modified psychophysical method of limits. With the exception of two patients (three eyes) whose Snellen acuity scores were 20/70, all observers had acuity scores of 20/30 or better. All subjects were corrected for astigmatism. Orientation, spatial frequency and temporal frequency interacted differently in determining contrast sensitivity in the two groups of observers. For the controls, an oblique effect was present for both the steady and counterphase modulated gratings of high spatial frequencies, and there was no orientation-dependent loss of sensitivity for low spatial frequencies. For the observers with MS, there was no oblique effect, but sensitivity was dependent on orientation for the low spatial frequencies. Most patients with MS had reduced contrast sensitivity, compared to the controls, at one or more orientations. Counterphase modulation increased sensitivity to the low spatial frequencies and decreased sensitivity to the high spatial frequencies for both normal controls and patients with MS. In patients with MS this effect of temporal modulation on contrast sensitivity was markedly enhanced.

The addition of a uniform increment of light to a high-contrast image that has been stabilized on the retina reveals marked perceptual nonlinearities. When the increment is small, the pattern appears in its original phase (OP), large increments produce an apparent phase reversal (APR), and intermediate increments may yield an apparently blank field or an oscillation of the apparent phase. In the present series of studies the threshold values used to produce a stable OP and APR were determined as a function of adaptation time before the application of the increment. The stabilized target had a luminance profile consisting of the difference of two Gaussians. A model of detection incorporating a multiplicative gain controlled by a filtered version of the stimulus was used to account for the occurrence of the OP and the APR and the transitory phenomena following the uniform increment. It is argued that the midpoint of the transition zone between the OP and APR, corresponding to blanking, enables us to estimate the shape of the step response function of the gain filter independently of the subsequent detection processes.

Orientation bandwidths of psychophysical channels in the human visual system were inferred from contrast thresholds for a special class of polar-separable, two-dimensional patterns. Detection thresholds for these patterns conformed to a model with linear filtering by orientation-selective channels followed by probability summation across these channels. The number of channels (6-8 pairs) and their half-bandwidths at half-sensitivity (approximately 17 degrees) did not differ at 4 and 10 cycles/degree. The results extend the many one-dimensional, linear system models of vision to two dimensions.

A pattern with a horizontal luminance profile described by the difference of Gaussians (DOG) was viewed under conditions of retinal image stabilization. When a uniform increment was applied after the image had disappeared, the pattern reappeared, but with the reversed phase. This phenomenon of apparent phase reversal (APR) is indicative of changes in local sensitivity. It was studied as a function of the time at which the increment was applied and the space constant of the DOG pattern. It was found that the threshold increment necessary to evoke an APR was an exponential function of time. A slight dependence on the spatial dimensions of the stimulus was also demonstrated. The data were examined according to a model of spatial vision that includes a gain that is inversely proportional to a spatially and temporally filtered version of the stimulus. The data provided estimates of the time constant and the spatial extent of the gain mechanism.

The effect of age on spatiotemporal contrast sensitivity at both threshold and suprathreshold levels was studied in 63 adults ranging in age from 13 to 67 years. Sensitivity for low spatial frequencies modulated at 0 to 15 Hz was not affected by age, but a progressive age-related elevation of threshold was found for combinations of high spatial and temporal frequencies. The magnitude of the effect ascribed to age on spatial frequency was larger than the effect of age on temporal frequency. For most combinations of spatial and temporal frequencies, elevation of thresholds started at approximately 45 years of age. No age-related effects were observed in a contrast-matching task performed at suprathreshold levels.

In 2 infant speech recognition experiments using trisyllabic sequences, the amount of redundancy within nontarget, context syllables was manipulated. Infants 6 1/2 months old were trained to discriminate the syllables [ba] versus [du] in contexts that were either redundant (e.g., [ko ba ko] or [ti ba ti]) or mixed (e.g., [ko ba ti] or [ti ba ko]) A visually reinforced head-turning procedure was employed. In Experiment 1, context was manipulated between subjects, but in Experiment 2 each subject received all 4 contexts (2 redundant, 2 mixed). Infants consistently recognized the familiar target in all contexts, but did so more successfully in redundant than in mixed trisyllablic contexts. These results suggest that amount of speech redundancy may be an important factor in infants' perceptual capabilities.