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There is growing recognition: (1) that sex (male and female) and sex hormones (androgens and estrogens) are important for physiologic functions outside those pertaining expressly to reproduction, and (2) that both classes of sex hormones are active in both sexes, and moreover are produced locally in non-gonadal tissues throughout the body. The visual system, in addition to being of tremendous inherent importance, is unique in a very distinctive way; it possesses an organ - the eye - having a window allowing its interior to be examined with exquisite precision and control in both laboratory and clinical settings. Plus, many diseases manifest in the eye or are exclusive to the eye. This special issue of Current Eye Research contains 12 review articles, each addressing a different topical area important for Sex, Eyes, and Vision: Male/Female Distinctions in Ophthalmic Disorders. Of course, the distinctions between topical areas are blurred, and the overlap between the various lines of knowledge and investigation likewise is substantial. Eye diseases can be both neurodegenerative and involve altered blood flow, for instance. In fact, the thematic overlap is greater yet, in that the articles for this special issue address matters of interest to clinicians and scientists who may identify more with women's health or sex & gender fields than with eye & vision fields. Nevertheless, because this special issue needs a home, the following 12 topical areas each have here their own dedicated review: age-related maculopathy, central nervous system function and cognition & perception, diabetic retinopathy, dry eye, glaucoma, inherited diseases, lens and cataract, neuro-ophthalmology, ocular blood flow, ocular inflammatory disorders, optical coherence tomography, and sex/gender eye care disparities. This overview article itself raises additional points expressly concerning: (1) the estrogen therapy timing hypothesis, and (2) breast cancer treatment with aromatase inhibitors.

This review concerns the effects on vision and the eye of medications prescribed at three phases of treatment for women with early-stage breast cancer (BC): (1) adjuvant cytotoxic chemotherapy, (2) adjuvant endocrine therapy, and (3) symptomatic relief. The most common side effects of cytotoxic chemotherapy are epiphora and ocular surface irritation, which can be caused by any of several different regimens. Most notably, the taxane docetaxel can lead to epiphora by inducing canalicular stenosis. The selective-estrogen-receptor-modulator (SERM) tamoxifen, long the gold-standard adjuvant-endocrine-therapy for women with hormone-receptor-positive BC, increases the risk of posterior subcapsular cataract. Tamoxifen also affects the optic nerve head more often than previously thought, apparently by causing subclinical swelling within the first 2 years of use for women older than ~50 years. Tamoxifen retinopathy is rare, but it can cause foveal cystoid spaces that are revealed with spectral-domain optical coherence tomography (OCT) and that may increase the risk for macular holes. Tamoxifen often alters the perceived color of flashed lights detected via short-wavelength-sensitive (SWS) cone response isolated psychophysically; these altered perceptions may reflect a neural-response sluggishness that becomes evident at ~2 years of use. The aromatase inhibitor (AI) anastrozole affects perception similarly, but in an age-dependent manner suggesting that the change of estrogen activity towards lower levels is more important than the low estrogen activity itself. Based on analysis of OCT retinal thickness data, it is likely that anastrozole increases the tractional force between the vitreous and retina. Consequently, AI users, myopic AI users particularly, might be at increased risk for traction-related vision loss. Because bisphosphonates are sometimes prescribed to redress AI-induced bone loss, clinicians should be aware of their potential to cause scleritis and uveitis occasionally. We conclude by suggesting some avenues for future research into the visual and ocular effects of AIs, particularly as relates to assessment of cognitive function.

Purpose: To determine whether the hill of vision for Short-Wavelength Automated Perimetry (SWAP) is shallower for women who consume phyto-oestrogen-rich foods than for women who do not. Methods: Visual field data were compared for two groups of healthy amenorrhoeic women 48–69 years-old with normal vision and not using hormone replacement: (1) 24 subjects who reported consuming soy and/or flax products and (2) 20 subjects who reported not consuming these products. Two types of 24-2 visual fields were measured: (1) Full Threshold SWAP and (2) a white-on-white (W/W) field obtained using a Swedish Interactive Threshold Algorithm (SITA Standard). Results: The reduction of SWAP sensitivity from the centre of the field (4 loci, mean eccentricity = 4.2°) to the periphery (20 loci, mean eccentricity = 21.9°) was less for soy/flax consumers than for nonconsumers, both with age-referencing (mean difference = 1.7 dB, p = 0.018) and without (p = 0.012). Corresponding distinctions existed for the SWAP – W/W difference, and there was minimal effect for W/W fields alone. The peripheral age-referenced SWAP sensitivities averaged 2.5 dB higher for consumers than nonconsumers (p = 0.022). Conclusion: The between-group distinctions are consistent with the possibility (derived from the women’s health literature) that phyto-oestrogens may counteract a decline of short-wavelength-sensitive cone-mediated response among postmenopausal women. These results suggest another potential application for SWAP outside its original intended purpose as a glaucoma test. Future studies should assess whether phyto-oestrogen consumption is most beneficial for women who are sufficiently young and/or not too far beyond menopause.

Winters-Stone KM, Torgrimson B, Horak F, Eisner A, Nail L, Leo MC, Chui S, Luoh S-W. Identifying factors associated with falls in postmenopausal breast cancer survivors: a multi-disciplinary approach. Objective To identify neuromuscular, balance, and vision factors that contribute to falls in recently treated breast cancer survivors (BCS) and explore links between fall risk factors and cancer treatment. Design Case-control plus prospective observation. Setting Comprehensive cancer center. Participants BCS (N=59; mean age, 58y) within 2 years of chemotherapy completion and/or on adjuvant endocrine therapy. Interventions Not applicable. Main Outcome Measures Objective measures of postural control, vision, and neuromuscular function included: (1) a sensory organization test (SOT), (2) a visual assessment battery, (3) muscle mass by dual energy x-ray absorptiometry, and (4) neuromuscular function with strength by repetition maximum, power by timed stair climb, and gait speed by 4m walk. Falls were self-reported for the past year (retrospective) and monthly for 6 months (prospective). Results Fifty eight percent of BCS reported falls in the past year. BCS with a history of falls had lower SOT scores with a vestibular deficit pattern in postural control ( P P Conclusions Results of this project suggest that balance disturbances of vestibular origin and delays in detecting low contrast visual stimuli are associated with falls in BCS. Future studies that track falls and fall risk factors in BCS from diagnosis through treatment are warranted, as are studies that can identify treatment-related vestibular dysfunction and altered visual processing.

Introduction The main purpose of this study was to determine whether the optic cups of tamoxifen users and anastrozole users differ in size, with the cups of the tamoxifen users being smaller. Methods Optic nerve head (ONH) topography was measured using a commercially available, confocal scanning laser ophthalmoscope for three populations of amenorrheic women ages 40–69 years: subjects using (1) tamoxifen (20 mg/day) or (2) anastrozole (1 mg/day) for ≤ 2 years as adjuvant therapy after successful primary treatment for breast cancer, and (3) control subjects with no breast cancer histories and not using any hormonal medication. All subjects had excellent visual acuity and healthy eyes, based on conventional photographic assessment. Results The cup volumes of the tamoxifen users were shown to be significantly smaller than the cup volumes of the anastrozole users, which were indistinguishable from normal. Because the cup volumes of the tamoxifen users decreased markedly with age at about 50 years and because anastrozole is indicated only for post-menopausal women, comparisons were reassessed for subjects older than 50 years. For these subjects, the cup volumes of the tamoxifen users averaged less than half of the volumes for each of the other two subject groups, and significant between-group differences existed in both the lateral (cup area) and axial (cup depth) directions. In contrast, any between-group differences at the ONH margin were small and not significant. Conclusions The results of this study suggest that the ONH be assessed biomorphometrically for tamoxifen users reporting visual change that cannot be attributed to non-tamoxifen causes. The ability of modern intraocular imaging techniques to reveal anatomic change on the order of tens of microns may be useful for assessing tamoxifen-induced effects occurring simultaneously elsewhere in the brain, particularly since the presence of small cups is consistent with the possibility of tamoxifen-induced astrocytic swelling.

This study was designed to evaluate the hypothesis that hormonal change can affect lower level light-adaptation processes, which are likely to be retinally based. Foveal visual sensitivities were measured across several menstrual cycles of four women not using hormonally acting medication and across several menstrual cycles of three women using a triphasic oral contraceptive. One woman, diagnosed with premenstrual syndrome (PMS), was a subject for both groups. Sensitivities were measured for a series of test wavelengths for 580-nm backgrounds of 2.0 and 4.0 log td. Of the six individuals tested, one had clear evidence of visual-adaptation changes occurring in phase with the menstrual cycle. Prior to using the oral contraceptive, this individual (the PMS subject) experienced changes of short-wavelength-sensitive (SWS)-cone-mediated sensitivities of up to about 1.4 log unit on the 4.0 log td background. Her SWS-cone-mediated sensitivities tended to be highest near ovulation and lowest premenstrually. Threshold-versus-illuminance (TVI) curves confirmed that the rate of sensitivity decrease with increasing background illuminance (i.e. the TVI slope) was greater premenstrually. The degree of background-induced desensitization within her middle-wavelength-sensitive (MWS)/long-wavelength-sensitive (LWS) cone pathways also appeared to vary cyclically, but the magnitude of the variation was smaller and the time course appeared to be different. When this subject began oral contraceptive use, the patterns of sensitivity change were all altered. None of the other five subjects experienced changes of SWS-cone-mediated vision that were cyclic and significantly adaptation-state dependent. However, there was evidence for a limited degree of cyclic adaptation change within the MWS/LWS cone pathways of at least one additional subject. We conclude that hormonal change can—for some unknown proportion of women—be linked to alterations of retinal function. However, the alterations are not the same for all visual pathways, and there are pronounced individual differences. The data also demonstrate that individuals' visual adaptation capabilities can vary substantially over periods of weeks.

To determine whether women using anastrozole (an aromatase inhibitor, which suppresses estrogen synthesis) are likely to have retinal hemorrhages.Fundus photographs were obtained for a study comparing effects on vision and the eye of anastrozole (1 mg/d) and tamoxifen (20 mg/d) for women receiving adjuvant endocrine therapy for early-stage breast cancer. Photographs (2 eyes per subject) were evaluated for hemorrhages by an ophthalmologist masked from identifying subject information. The presence of hemorrhages was assessed for 35 anastrozole users, 38 amenorrheic tamoxifen users, and 53 amenorrheic (peri- or postmenopausal) control subjects not using any endocrine medication. The age range was 43 to 69 years; only subjects reporting normal vision and healthy eyes were recruited. Photographs from 36 tamoxifen users from a previous study also were assessed. Views of the fundus extended appreciably beyond the posterior pole for all tamoxifen and anastrozole users, and for 38 of the control subjects. Photographic assessments were compared with medical history and blood pressure data, and optical coherence tomography was used for quantifying aspects of foveal shape that might be affected by vitreoretinal traction.Four anastrozole users and no contemporaneous tamoxifen users but one previously tested tamoxifen user had retinal hemorrhages, in each case within the posterior pole. Two anastrozole users had a flame hemorrhage (in the retinal nerve fiber layer), and two had a blot hemorrhage (deeper in the retina). No control subjects were observed to have hemorrhages.Anastrozole use appears to be associated with an increased prevalence of retinal hemorrhages. The hemorrhages may mark systemic vascular compromise resulting from estrogen depletion, and/or they may be consequences of vitreoretinal traction resulting from estrogen depletion. They may also depend on the use of medications for controlling common anastrozole-induced side effects. Prospective studies need to be conducted with larger numbers of subjects.

Purpose To test the hypothesis that differences between short-wavelength automated perimetry (SWAP) and white-on-white visual field sensitivities are related to between-individual variation in the visual adaptation properties of SWS cone pathways. Methods Twenty-six healthy amenorrheic (peri- or postmenopausal) women not using hormonal medication were tested. Subjects ranged in age from 48 to 68 years. They were tested by using foveal increment-threshold techniques and also with two types of 24-2 visual field tests: a full-threshold SWAP blue-on-yellow (B/Y) test and a white-on-white (W/W) test obtained using a Swedish Interactive Threshold Algorithm (SITA Standard). The age-corrected sensitivity differences between the two types of visual fields were compared against foveal measures of visual sensitivity and adaptation, which were obtained psychophysically using dim and bright yellow backgrounds. All measurements for each subject were made at a single testing session. The comparisons were made for the entire visual field and for separate portions of the visual field. The analyses also included pupil size data obtained during visual field testing. Results The B/Y minus W/W (B/Y - W/W) mean deviation difference was described (R = 0.80) by a multilinear model with three significant factors: (1) an adaptation factor and (2) a baseline sensitivity factor, each derived from the foveal psychophysical data for short-wavelength test stimuli, and (3) a pupil size factor, as recorded for SWAP. The total deviation differences in the periphery of the visual field (approximately 22 degrees from fixation) were described (R = 0.87) by a model with four significant factors, the fourth being an "eccentricity factor" describing the rate of change of the B/Y - W/W total deviation difference measured as a function of increasing retinal eccentricity approximately 9 degrees -17 degrees from fixation. More than 40% of the variance in the B/Y - W/W mean deviation differences was accounted for either directly or indirectly (via effects of pupil size) by variations in adaptation to the yellow background used for SWAP. Conclusions Much of the extra variability in SWAP sensitivities for a select group of healthy women can be accounted for by differences in the degree of desensitization induced by the yellow background used for SWAP. For clinical practice, pupil status (dilated or undilated) should be altered only with caution from one SWAP testing session to another.

There is a substantial literature showing that the selective estrogen receptor modulator tamoxifen can block swelling-activated chloride channels, such as those in astrocytes. This study aimed to test the hypothesis that anatomic characteristics consistent with swelling may be measured within the optic nerve head (ONH) of tamoxifen users whose ONH appearance is considered within normal limits.Indices of ONH topography were measured using the Heidelberg Retina Tomograph II (HRT) for two populations of women ages 40-69 years: (1) subjects using tamoxifen (20 mg/day) as adjuvant therapy after successful primary treatment for breast cancer and (2) control subjects not using any hormonal medication. All subjects had excellent visual acuity (with 20/20 or better in the test eye), and all appeared to be free of eye disease, as based on conventional photographic assessment. The study design was cross-sectional. The various ONH indices were assessed as functions of the duration of tamoxifen use.The optic cups of short-term tamoxifen users (or=2 years) were significantly smaller in both the lateral and axial directions than the optic cups of the control subjects. Of the 27 short-term users, 23 had cup volumes smaller than the median value for the control subjects. The cup sizes of long-term users (2 years,or=5 years) were not distinguishable from those of the control subjects. The presence of small cups among short-term users did not depend on subjects' medical histories prior to tamoxifen use. Disk margin indices were not related significantly to the duration of tamoxifen use.Small cup sizes consistent with localized subclinical swelling are not rare among short-term tamoxifen users. Thus, small cups are not likely to be a manifestation of a cumulative-dose toxicity. Instead, they probably result from other causes, possibly involving the action of tamoxifen on estrogen receptors. Further investigation with longitudinal and interventional methodologies is needed to definitively interpret the results.

This study compared color appearance data for two populations of middle-aged women: (1) women using the selective estrogen receptor modulator tamoxifen as adjuvant therapy following successful treatment for early-stage breast cancer, and (2) healthy amenorrheic (peri- or post-menopausal) control subjects not using any hormonally acting medications. A 3-alternative forced-response paradigm (with “blue”, “lavender”, or “white” as the allowable responses) was used for assessing the perceived color of 440-nm foveal test stimuli superimposed on a larger 3.6 log td 580-nm background. In contrast to the control subjects, the majority of tamoxifen users described the test stimuli as “white”, whether at threshold or slightly suprathreshold. Threshold-sensitivity measurements themselves appeared less effective for distinguishing between subject groups. The results show that a simple color-naming procedure can reveal alterations of foveal short-wavelength-sensitive cone-mediated visual function that are common among tamoxifen users.

Background/aims: Oestrogen receptors (ORs) have been reported to be present in the retina, and the selective oestrogen receptor modulator tamoxifen has been reported to affect colour vision. This study aimed, therefore, to determine whether standard doses of tamoxifen affect visual sensitivities mediated via short wavelength sensitive (SWS) cones. Methods: Two types of visual fields were measured for middle aged women who were being treated with 20 mg of tamoxifen daily as adjuvant therapy for early stage breast cancer. Visual fields were measured using short wavelength automated perimetry (SWAP) and frequency doubling perimetry (FDP). For SWAP, 24-2 visual fields were analysed. No subjects had tamoxifen retinopathy or other eye disease. For each type of visual field, mean deviations (MDs) were assessed as a function of the duration of tamoxifen use, using a cross sectional design. In addition, the difference between the two types of MDs was computed after standardisation of each type of MD separately, and this difference itself was evaluated as a function of the duration of tamoxifen use. Duration dependent changes for SWAP were further evaluated as a function of eccentricity within the visual field, and the visual field data were compared with foveal data obtained psychophysically. Results: SWAP sensitivities depended on the duration of tamoxifen use. Subjects who used tamoxifen for about 2 years or less were significantly more likely than subjects who had longer use to have high MDs. The difference between the standardised SWAP and FDP MDs likewise was significantly related to the duration of use, whereas duration of use effects for FDP itself were reduced or absent. Although the duration of use effect observed for SWAP was strongest in the peripheral portion of the visual field, there was evidence of changes in SWS cone mediated vision even at the fovea. Conclusion: Standard dosages of tamoxifen can affect SWAP visual fields. The effects of tamoxifen are not equivalent for SWAP and FDP, indicating that tamoxifen affects some types of visual pathways preferentially or selectively. SWS cone pathways, in particular, are affected. SWAP appears able to reveal effects of tamoxifen occurring years before completion of the standard 5 year regimen of use.

The study had two main purposes: (1) to determine whether the foveal visual sensitivities of people treated for high blood pressure (vascular hypertension) differ from the sensitivities of people who have not been diagnosed with high blood pressure and (2) to understand how visual adaptation is related to standard measures of systemic cardiovascular function. Two groups of middle-aged subjects--hypertensive and normotensive--were examined with a series of test/background stimulus combinations. All subjects met rigorous inclusion criteria for excellent ocular health. Although the visual sensitivities of the two subject groups overlapped extensively, the age-related rate of sensitivity loss was, for some measures, greater for the hypertensive subjects, possibly because of adaptation differences between the two groups. Overall, the degree of steady-state sensitivity loss resulting from an increase of background illuminance (for 580-nm backgrounds) was slightly less for the hypertensive subjects. Among normotensive subjects, the ability of a bright (3.8-log-td), long-wavelength (640-nm) adapting background to selectively suppress the flicker response of long-wavelength-sensitive (LWS) cones was related inversely to the ratio of mean arterial blood pressure to heart rate. The degree of selective suppression was also related to heart rate alone, and there was evidence that short-term changes of cardiovascular response were important. The results suggest that (1) vascular hypertension, or possibly its treatment, subtly affects visual function even in the absence of eye disease and (2) changes in blood flow affect retinal light-adaptation processes involved in the selective suppression of the flicker response from LWS cones caused by bright, long-wavelength backgrounds.

The selective suppression of flicker response from LWS cones has been investigated with two approaches. One approach has emphasized the use of light-adaptation conditions, and the other has emphasized the use of dark-adaptation conditions. In both cases, stimuli are arranged to restrict or exceed the ability of adaptation processes to maintain an afferent flicker response, and long-wavelength stimuli are used to overload spectrally opponent processes. By integrating these two approaches, this study shows that diverse manifestations of flicker response suppression can be closely related mechanistically. For instance, the steep flicker TVI slopes that resulted from superimposing temporally modulated (100% contrast) test stimuli on flashed backgrounds corresponded to the disappearance of flicker that resulted from increasing the time-averaged illuminance of temporally modulated stimuli (contrast x100%) that were flashed alone in an otherwise dark field. For the stimulus parameters of this study, flicker response suppression was more evident for small (19' diameter) than for large (1 degree diameter) stimuli. However, flicker response suppression was elicited reliably for both sizes by adding a spatially coincident short-wavelength stimulus to the interstimulus interval between presentations of the long-wavelength stimuli. By showing that temporal contrast can be treated as an independent variable for an important set of test/background stimulus combinations, the results of this study make it possible to investigate the means by which changes of contrast gain help to maintain flicker response as assessed in a conventional flicker TVI paradigm. The reduced degree of suppression for relatively large stimuli probably is related to the increased action of spatially extensive contrast gain-control processes. These contrast gain-control processes might not act independently of spectrally opponent processes.

OBJECTIVE To establish normative relations between measures of visual function and cardiovascular variables that are important for age-related disease, including various forms of glaucoma. METHODS Foveal flicker sensitivities, resting blood pressures and heart rates, and intraocular pressures were measured in 18 individuals aged 40 to 68 years. All subjects had 20/20 or better visual acuity in the test eye and no evidence of eye disease or glaucoma suspicion on clinical evaluation and medical history. No subjects were using medication to lower blood pressure. Flicker sensitivity was measured by increasing the illuminance of a fully modulated 20-Hz test stimulus until flicker was perceived. Two test-background stimulus combinations were used: a 570-nm ("yellow") test on a predominantly long-wavelength ("magenta") background and a 580-nm ("yellow") test on a 580-nm ("yellow") background. The illuminance of the yellow background was dimmer than that typically used for short-wavelength automated perimetry, whereas the illuminance of the magenta background was greater. RESULTS The 2 flicker sensitivity measures were distinguished by the strong dependence of the magenta background measure on the ratio of mean arterial blood pressure to heart rate. Log flicker sensitivity on this background generally could be modeled as a linear combination of age, intraocular pressure, and ratio of mean arterial blood pressure to heart rate. The optimal model accounted for 84% of the variance (R = 0.92) from all but 2 outlying individuals. After age and intraocular pressure effects were partialed out, an increasing ratio of mean arterial blood pressure to heart rate was strongly associated with decreasing flicker sensitivity. CONCLUSIONS Reduced cardiovascular function impacts the ability of the normal visual system to adapt and regulate flicker sensitivity. Elevated intraocular pressure and increased age reduce flicker sensitivity relatively uniformly across a range of stimulus conditions. Because the ratio of mean arterial blood pressure to heart rate equals total peripheral vascular resistance multiplied by cardiac stroke volume, and because total peripheral resistance is determined largely at the arterioles, it is likely that even modest changes in arteriolar function are associated with measurable alterations of visual function. Arch Ophthalmol. 2000;118:1049-1055

For a wide range of temporal frequencies and modulation depths, stimulus conditions can be chosen so that flicker threshold decreases abruptly (i.e. flicker response becomes enhanced) with small increases of adaptation field illuminance [1]. At test illuminances sufficiently above this reduced flicker threshold, flicker again becomes subthreshold [1]. The adaptation field illuninances at which flicker response is enhanced or suppressed depend strongly on the temporal frequency and modulation depth of the test [1]. In the present report, data are presented to show that for both enhancement and suppression, reductions of modulation depth for 11 Hz stimuli can be operationally equivalent to increases of temporal frequency for fully modulated, higher frequency flicker.

Foveal sensitivities were measured after onset of adapting background fields for each of the following four groups of subjects aged 40-70 years: (1) low-tension glaucoma subjects with minimal field loss in the test eye, (2) primary open-angle glaucoma subjects with minimal field loss in the test eye, (3) normal control subjects, and (4) subjects originally enrolled as control subjects but subsequently found, on the basis of masked clinical evaluation, to be suspect for glaucoma despite ostensibly normal intraocular pressures. We found that the desensitization of a short-wavelength-sensitive-cone-mediated response after onset of a 580-nm background field was diminished from that of normal observers for low-tension glaucoma subjects but not for primary open-angle glaucoma subjects. The desensitization was also diminished for a glaucoma-suspect subjects aged 60-70 years. In contrast, the flicker sensitivity instabilities that persisted after onset of a long-wavelength background field for the majority of subjects with primary open-angle glaucoma [J. Glaucoma Suppl. 3, S19 (1994)] occurred only infrequently among the other subject groups. These results imply that glaucoma often involves the fovea, probably by affecting retinal subtractive adaptation processes, although with different consequences for different types of glaucoma. The results also suggest that undiagnosed low-tension glaucoma may not be rare in the general aging population.

The purpose of this study is to test the hypothesis that visual adaptation can be affected in glaucoma, particularly in normal (or "low") tension glaucoma. More specifically, this study aims to test the hypothesis that by taxing the adaptation capabilities of eyes with normal-tension glaucoma but only minimal field loss, time-dependent abnormalities can be elicited at the fovea.

This study examined the detectability of flicker for small long-wavelength foveal test stimuli centered within larger long-wavelength surround stimuli. Flicker visibility was evaluated as a function of surround and test illuminance and as a function of test wavelength, of the time elapsed following test or surround onset, and of surround dimensions. Consistent with prior flicker threshold-versus-illuminance results [ Vision Res.26, 917 ( 1986)], flicker threshold decreased abruptly once the surround illuminance became sufficiently great. However, as test illuminance was increased above flicker threshold, flicker again vanished. Flicker reappeared at still higher test illuminances, as middle-wavelength-sensitive (M-) cone-mediated flicker threshold was exceeded. Meanwhile, the time required for the surround to render flicker visible increased at a rapidly accelerating rate with decreasing surround illuminance; it increased at a more sporadic rate with increasing test illuminance. At bright enough surround illuminances, flicker did not vanish with increasing test illuminance. These and other results are compatible with a framework derived from previous dark-adaptation data8 [ Vision Res.32, 1975 ( 1992)]. In that framework the test stimulus itself induces losses of flicker sensitivity by sufficiently perturbing retinal response during states or stages of adaptation that fail to cause spectrally antagonistic processes to redress that perturbation adequately. The relevant adaptation processes, which can require minutes, involve an adaptation pool that includes (and is affected by) the test stimulus.

This study examined the detectability of flicker (18 Hz, 100% modulation) for small (13’ diameter) foveal test stimuli (656 nm) centered within long-wavelength (660 nm) annular surround stimuli (inner diam. = 18’, outer diam. = 1°).

This study of visual function in the elderly evolved from previous studies mainly on the basis of one simple premise: namely, that detection of functional deficit due to glaucoma may be enhanced by testing the eye while it responds near the limit of its operating range. To achieve this state, we measured flicker sensitivity while the eye was in the process of adapting to somewhat extreme (but harmless) stimulus conditions.

Longitudinal changes of visual function over 18 months were evaluated for two elderly populations: (1) people with unilateral exudative age-related macular degeneration (AMD) in the fellow eye, and (2) people with no history of eye disease. The former population was divided into two subgroups, high-risk and low-risk, on the basis of fundus appearance at baseline. Several visual functions were tested: (a) Losses of short-wavelength-sensitive (S) cone mediated sensitivity over 18 months were significantly greater for high-risk eyes than low-risk eyes; some low-risk eyes appeared to have supranormal increases of S cone mediated sensitivity. Normative color-naming data established that the test stimulus at S cone mediated threshold often appeared desaturated, especially for elderly women; (b) For both high-and low-risk eyes, foveal absolute sensitivity tended to change little over 18 months; appreciable decreases were observed only for several high-risk eyes; (c) For large-field Rayleigh color-matches, the matching ranges widened significantly more for high-risk eyes than low-risk eyes; for small-fields, the data were more complicated. Shrinking of the small-field matching range was associated with midmatchpoint shifts in the protan direction. These results, plus the rejection of all potential Rayleigh color matches by some individuals, have implications for studies that seek to relate color vision genotype to phenotype.

The losses of flicker sensitivity that occur during dark adaptation following extinction of a bleach depend greatly on the test stimuli that are used to measure those losses. Generally, the larger the test size is for a given test wavelength, the later is the loss of flicker sensitivity; for sufficiently large tests, losses become progressively more gradual. Similarly, the shorter the test wavelength is (between about 660 and 580 nm) for a given test size, the later is the loss of flicker sensitivity; for sufficiently short test wavelengths, losses become progressively more gradual. Although the pattern of flicker sensitivity loss as a function of test size is the same both foveally and parafoveally, foveal losses occur later and/or more gradually for a given test stimulus. The results suggest that losses of flicker sensitivity occur when spectrally antagonistic response(s) to the test are no longer adequate to maintain the flickerresponse to that test. The results suggest also that the adequacy of such spectral antagonism depends on the local adaptation state of the retina, which becomes increasingly more light-adapted with increasingly large test size.

There are many reasons for studying the ways in which visual function changes with disease. One very general reason is to help understand how the visual system works. More specifically, by testing diseased eyes it may be possible to evaluate the generality of conclusions derived from studies of healthy eyes. This type of evaluation may help reveal implicit assumptions that underlie studies of normally functioning visual systems, which typically are investigated using small-sample designs.

We analyze adaptation processes responsible for eliciting and alleviating flicker response suppression, which is a class of phenomena characterized by the selective reduction of visual response to the ac component of a flickering light. Stimulus conditions were chosen that would allow characteristic features of flicker response suppression to be defined and manipulated systematically. Data are presented to show that reducing the sinusoidal modulation depth of an 11-Hz stimulus can correspond precisely to raising the temporal frequency of a fully modulated stimulus. In each case there is a nonmonotonic relation between flicker response and dc test illuminance. The nonmonotonic relation cannot be explained by adaptation models that postulate multiplicative and subtractive adaptation processes followed by a single static saturating nonlinearity, even when temporal frequency filters are incorporated into such models. A satisfactory explanation requires an additional contrast gain-control process. This process enhances flicker response at progressively lower temporal response contrasts as the illuminance of a surrounding field increases.

This study examined the detectability of flicker for small foveal long-wavelength test stimuli centered within surrounding long-wavelength annular adaptation stimuli. Flicker threshold-versus-illuminance (tvi) curves were analyzed for four different test-stimulus waveforms--sine-wave, square-wave, and rapid-on sawtooth and rapid-off sawtooth flicker--at temporal frequencies ranging from 12 to 21 Hz and at temporal modulation depths ranging from approximately 50% to 100%. For all stimulus combinations that were examined involving temporal frequencies above 12 Hz, the resultant flicker tvi curves shared the following characteristic features: First, at operationally dim surround illuminances, there was always a single elevated threshold for detection of flicker. Second, some surround illuminance always could be found for which flicker threshold decreased abruptly, typically by approximately 1.5 log units within 0.1 log unit of surround illuminance increase. Third, when test illuminance was incremented above this lower flicker threshold, flicker always vanished; when test illuminance was incremented still further, flicker reappeared. Finally, at sufficiently bright surround illuminances flicker did not disappear with increasing test illuminance. Although these effects held for all waveforms, the abrupt decrease of flicker threshold occurred at brighter surround illuminances for sawtooth than for sine-wave flicker, and at brighter surround illuminances for sine-wave than for square-wave flicker, at least for fully modulated waveforms (of a given temporal frequency). Moreover, when modulation depth was adjusted so that any two different waveforms had the same first-harmonic contrast, the resultant flicker tvi curves became identical when plotted as first-harmonic amplitude versus surround illuminance. This identity held for any given temporal frequency, even though the flicker tvi curves for 12-Hz fully modulated sine-wave or square-wave flicker did not manifest flicker response suppression, whereas the flicker tvi curves for sawtooth flicker did. These and other results imply that the first-harmonic contrast of the test stimulus fully determines the shape of the entire flicker tvi curve and that the dc component of the test stimulus helps to cause flicker response suppression. The results also demonstrate that first-harmonic equivalence is only a necessary, not a sufficient, condition for linearity.

This study tested the hypothesis that (a) evidence of foveal visual dysfunction could be elicited in glaucoma subjects by measuring flicker sensitivity as a function of time after onset of an adapting field for a suitably chosen set of test and adaptation parameters and that (b) such dysfunction would be related to high blood pressure. Three groups of subjects were tested: (a) subjects with primary open-angle glaucoma but only minimal field loss, (b) normal control subjects, and (c) control subjects found to be suspect for glaucoma. The protocol included measurement of pulse rate and blood pressure, administration of Humphrey 30-2 visual fields and optic nerve head photography, and administration of a battery of psychophysical tests in Maxwellian view. This battery included a test of flicker sensitivity measured at middle wavelengths as a dynamic function of time after onset of a long-wavelength adapting field. The dynamic light-adaptation functions of subjects with glaucoma were much more likely to be unstable than were the corresponding functions of normal subjects. In addition, the dynamic light-adaptation functions of subjects with high blood pressure for their pulse rate were significantly less stable than the correspond ing functions of subjects without high blood pressure for their pulse rate. Moreover, the ratio of mean arterial pressure to pulse rate was significantly less for normal subjects than for either glaucoma subjects or for glaucoma-suspect subjects. We infer that among people with primary open-angle glau coma but with only minimal field loss, there often is foveal dysfunction associated with cardiovascular disease. Evidence of such dysfunction appears to require the use of stimulus conditions that tax the ability of the visual system to respond appropriately.

Subjects wore a long-wavelength passband filter over one eye for 1 week. As a consequence, for that eye only, sensitivity to long-wavelength stimuli declined, unique yellow shifted to longer wavelengths, and scotopic stimuli acquired a strikingly bluish appearance. These results make it very likely that long-term exposure to a long-wavelength world can induce relatively prolonged (at least hours) postreceptoral adaptation.

Dynamics of foveal light adaptation for vision mediated via short-wavelength-sensitive (SWS) cones were compared for two groups of healthy amenorrheic (peri- or post-menopausal) women not using hormonal medication. Each subject was assigned to a group based on the color name-"lavender" ( approximately 2/3 of all subjects) or "white" (approximately 1/3 of all subjects)-chosen in a forced-response paradigm to best describe a threshold-level 440-nm test presented on a larger 3.6 log td 580-nm background that had been viewed for approximately 5 min. During the first 20-30s after this 3.6 log td background abruptly replaced a much dimmer background, the threshold elevations (relative to the steady-state levels measured at approximately 5 min) were significantly greater for the lavender-naming subjects than for the white-naming subjects. However, exponential rates of recovery were indistinguishable for the two groups. A viable interpretation is that the gain of the visual response at background onset is greater for lavender-naming subjects than for white-naming subjects at or distal to a site where responses from middle-wavelength-sensitive and long-wavelength-sensitive (MWS and LWS) cones oppose responses from SWS cones. In addition, the color names derived from foveal testing were related systematically to extrafoveal sensitivities measured with Short Wavelength Automated Perimetry (SWAP), in a manner suggesting that response gain and/or response speed may be greater for lavender-naming subjects in the direction of increased SWS response also. Evidence from other subject populations suggests that the choice of color name and the dynamics of visual response each can be affected by alterations (particularly reductions) of estrogen synthesis and response.

Systematic differences of foveal sensitivity exist among people aged sixty and older who have good acuity and good ocular health in each eye. For example, absolute threshold to 660-nm tests increases with age. The rate of increase is ~0.1 log units per decade. Not surprisingly, blue cone threshold also Increases with age. However, the rate of increase of blue cone threshold appears to be greater for women than for men. Some visual functions do not change with age, at least when change is defined cross sectionally. For example, the rate of threshold recovery following a bleach does not change with age. Nevertheless, the rate of threshold recovery following a bleach can be a sensitive indicator of retinal health, even among eyes which have 20/20 acuity. Specifically, eyes with 20/20 acuity having many macular drusen have slow rates of recovery, at least for that population of eyes whose fellow eye has exudative aging macular degeneration (AMD). Eyes with good acuity but whose fellow eye has exudative AMD tend to have high absolute thresholds at 660 nm and high blue cone thresholds. The elevation of blue cone threshold is greater for 1° than for 3° stimuli. A disproportionate number of these eyes do not have measurable color match area effects, implying that they have low effective foveal cone photopigment densities. Surprisingly, however, red/green color discrimination is no worse for these 20/20 eyes whose fellow eye has exudative AMD than for normal 20/20 eyes.

Sensitivity to an 18-Hz 20-min of arc test stimulus following a 5-min duration bleach depends on the spectral characteristics of both the bleach and test. When the test stimulus is 656 nm and the bleach is ~60,000 to 70,000 td, equating different wavelength bleaches for L cone quantum absorption causes dark adaptation curves to be identical or similar. Conversely, varying the test wave length following a 660-nm bleach causes profound differences in the shapes of the dark adaptation curves. When the test is 656 nm, sensitivity drops by ~1.8 log unit within ~30 s or less at ~3 min or later after extinction of the bleach. When the test is 540 (one subject) or 470 nm (another subject), sensitivity drops by ~0.7 log unit within ~40 s or less ~1 min or less after extinction of the bleach. When the test is 600 nm, sensitivity decreases gradually by ~1.0 log unit over a span of 10 min or more. To minimize rod-cone lateral interactions, dark adaptation curves were in all cases obtained in the presence of 480-nm annular surrounds (1° i.d.), which followed bleaches of at least 30,000-scotopic td illuminance.

Rats were forced to drink increasingly strong concentrations of ethanol for 7 weeks and were then divided into two groups. One group was given a choice between two neutral flavors, the drinking of one of which was paired with an equal volume of intragastric alcohol. The drinking of the other was paired with an equal volume of water. The second group was given an oral choice between alcohol and water. Control rats were kept under identical conditions for 7 weeks, except that they were given no alcohol. Some of the controls were also given a choice between two neutral flavors when one of these was paired with intragastric alcohol. Others were given an oral choice between alcohol and water. Rats forced to drink alcohol drank more of the neutral flavor paired with intragastric alcohol than did the controls not previously given alcohol. On the other hand, rats forced to drink alcohol and then given an oral choice between alcohol and water drank substantially less alcohol than did the control rats with no previous experience of alcohol that were also given an oral choice between alcohol and water. It was concluded that forced drinking of alcohol produces a conditioned aversion to the taste and smell of alcohol and also a tolerance to the after-effects of alcohol. However, such tolerance will only lead to voluntary intake of alcohol if intake bypasses the sensory effects of alcohol for which a conditioned aversion had developed during the period of forced drinking.

Filtration of argon laser light to eliminate the blue wavelengths and create a green-only light may be clinically useful in treating macular lesions. To that end, an inexpensive, easy method of modifying a posterior pole contact lens for use with any ophthalmic argon laser to allow only green, not blue, laser light to be used for macular photocoagulation is described.

Flicker sensitivity to a small foveal test stimulus can decrease appreciably during the period of dark adaptation that follows extinction of a bleach. For 20 min diameter, long wavelength tests that followed 70% L cone bleaches of various wavelengths, 18 Hz flicker sensitivity decreased precipitously (i.e. within about 45 sec) by about 1.5–2.0 log units beginning at about 100–200 sec following extinction of the bleach. For short wavelength tests that followed long wavelength bleaches, the corresponding precipitous losses of flicker sensitivity were relatively small and early; flicker sensitivity decreased by about 0.6–1.0 log units begining no later than 60 sec following extinction of the bleach. Whenever flicker sensitivity decreased precipitously, the losses of flicker sensitivity were followed by plateaus of M cone dominated flicker sensitivity. For combinations of test and bleaching wavelengths that did not cause flicker sensitivity to decrease precipitously, flicker sensitivity instead decreased gradually over a prolonged period of time, and incorporated a substantial L cone contribution. The precipitous suppression of flicker sensitivity found for certain combinations of bleaching and test wavelengths appears to depend on the action of a broadly tuned, red-green spectrally opponent process.

While studying the aging visual system for the intended purpose of understanding age-related macular degeneration, we have employed a battery of tests that has included measures of 20-Hz flicker sensitivity on chromatic backgrounds. Unexpectedly, we found that more than 10% of people older than age 70 in a large control group had profound reductions of flicker sensitivity, more than 10 standard deviations from the mean norm, for at least one of the two background conditions used to measure flicker sensitivity. These people were more likely to be taking cardiovascular medication and/or have glaucotomous optic nerve head change than people without profound reductions. However, their intraocular pressures were within normal limits at the time of testing. Following these observations, we measure chromatic adaptation flicker tvi curves of young normal subjects, using 750-ms duration test stimuli. We found that on long wave length backgrounds flicker tvi slopes became great (~5) between 4.5 and 4.7 log td at 540 nm, but were near unity at 640 nm. The steep slopes coincided with the breakdown of effective M cone isolation. The results from young people suggest that profound losses of flicker sensitivity associated with low tension glaucoma could depend on spectrally opponent saturation. Preliminary results from people with low tension glaucoma are consistent with that possibility.

The leading cause of new blindness among people aged 60 or older is age-related macular degeneration (AMD) (1). There are two forms of AMD, exudative and atrophic. Most AMD-related blindness is due to the exudative form (2), which is the potentially treatable form. When an exudative lesion is sufficiently far from the foveola, that lesion may be treated by application of laser photocoagulation (3,4). Because the distance of the exudative lesion from the foveola often decreases rapidly with time after presentation of initial symptom. (5), prompt treatment after presentation of symptoms is essential in order to maximize that treatment's chance of success. Because initial symptoms can be missed or overlooked (6), it is important that individuals know whether or not they are at especially great risk for developing exudative AMD.

The Farnsworth Dichotomous Test for Color Blindness (Panel D-15), often called simply the D-15 test, is an easy to administer arrangement test which is designed to fail those individuals having severe color discrimination loss. The test is very successful at detecting and classifying congenital dichromacy or anomalous trichromacy in which color discrimination is very poor. Because the test is readily obtainable and is easy to administer and score, it often is used to ascertain visual loss due to acquired defects or changes. When used in this manner, either tritan errors (those errors associated with a decrease of blue cone mediated discrimination) or errors associated with a diffuse loss of chromatic discriminative ability are of interest. This paper discusses briefly the relationship between these types of errors and blue cone sensitivity as measured with a threshold task in a population of normal individuals aged sixty and older.

We have shown previously that the losses of foveal flicker sensitivity following extinction of a bleach can be either precipitous or gradual, depending critically on the spectral characteristics of both the bleach and test.1 These losses, measured with 18-Hz flicker, also depend on the size and retinal location of the stimuli. At an eccentricity of 4.5°, precipitous losses of sensitivity to 20′ diam tests occur earlier than they do at the fovea. As the parafoveal tests are enlarged, the precipitous losses of sensitivity occur later [e.g., at 1 vs 3 min for 20′ vs 1° diam long wavelength tests that follow extinction of a 4.90-log troland (Td) 540-nm bleach]. As the tests are enlarged more (e.g., to 2° following extinction of the 540-nm bleach), the losses become less precipitous, often resembling the gradual losses found at the fovea for certain spectral combinations of bleaches and 20′ diam tests (the same diameter tests we used previously). On the other hand, when stimuli which result in gradual losses foveally (e.g., a 20′ diam 578-nm test following a 580-nm 4.85-log Td bleach) are moved to the parafovea, the losses can become early and precipitous. Making these foveal tests smaller can also result in precipitous losses. The data suggest that (a) precipitous losses are associated with relatively small tests, while delayed or gradual losses are associated with relatively large tests and (b) the relevant spatial dimensions depend on the spectral parameters of the bleach and test as well as on the retinal locus.

The rate of decrease of the logarithm of visual threshold at the fovea to a long-wavelength test after extinction of a 580-nm bleach is not described by an exponentially shaped function. Instead, there is a period of time during dark adaptation about midway between extinction of the bleach and complete recovery of sensitivity when threshold does not continue to decrease. The duration of this period can be up to ~1 a min depending on the illuminance of the bleach. The departure from an exponential time course of recovery is greater when the test stimulus is a disk which is defocused on the retina and sinusoidally modulated at 1 Hz than when the test stimulus is a disk which is focused on the retina and either flashed for 160 msec or sinusoidally modulated at 1 Hz. Losses of sensitivity with time are sometimes apparent about midway through recovery when the test is a defocused disk which is modulated sinusoidally at 1 Hz. When the test stimulus is a disk which is focused on the retina and flashed for 160 msec, sensitivity to test stimuli >580 nm may be described as changing successively from subtractive to additive to subtractive types of combination of L and M cone sensitivities.

• A human subject whose photoreceptors were deduced to be oriented toward a common point near the center of the eyeball rather than toward a common point within the pupil was reexamined three years after the original testing. The photoreceptors were still found to be oriented in the aforementioned anomalous fashion, as deduced from the peak locations of Stiles-Crawford (S-C) functions measured at various retinal locations, as before. Patching the eye for a week caused little or no flattening of the S-C functions.

With the eye adapted to (representative) colored backgrounds, 15-Hz flicker photometry and flicker thresholds yielded spectral-sensitivity curves identical within error. Flicker photometry is the more precise measure.

Flicker photometric equivalence is both additive and transitive when the test and standard are alternated upon a relatively more intense colored background. When the balance of red versus green cone excitation from the background is unequal, the contribution of one cone type to flicker photometric spectral sensitivity may be depressed in relation to that of the other by at least 1 order of magnitude more than Weber's law predicts. The resultant spectral sensitivity is determined predominantly by only one class of cone. The cone spectral sensitivities of normals are then seen to be the same as those of dichromats, although there is some individual variation. A model is developed to explain this surprising phenomenon.

We find that additivity of trichromatic color matches holds, even in parafoveal vision, for most observers if rods are prevented from seeing the stimuli. Some heterozygous women are exceptions. The failure of the additivity law for these women implies that their eyes contain more than three types of cone with different spectral sensitivities.

By using violet backgrounds we selectively altered blue-cone sensitivity but found no change in flicker photometric sensitivity. This indicates that blue cones do not contribute to luminance as defined by flicker photometry.