Ronald S. Harwerth

Linking Structure and Function in Glaucoma

The glaucomas are a group of relatively common optic neuropathies, in which the pathological loss of retinal ganglion cells causes a progressive loss of sight and associated alterations in the retinal nerve fiber layer and optic nerve head. The diagnosis and management of glaucoma are often dependent on methods of clinical testing that either, 1) identify and quantify patterns of functional visual abnormality, or 2) quantify structural abnormality in the retinal nerve fiber layer, both of which are caused by loss of retinal ganglion cells. Although it is evident that the abnormalities in structure and function should be correlated, propositions to link losses in structure and function in glaucoma have been formulated only recently. The present report describes an attempt to build a model of these linking propositions using data from investigations of the relationships between losses of visual sensitivity and thinning of retinal nerve fiber layer over progressive stages of glaucoma severity. A foundation for the model was laid through the pointwise relationships between visual sensitivities (behavioral perimetry in monkeys with experimental glaucoma) and histological analyses of retinal ganglion cell densities in corresponding retinal locations. The subsequent blocks of the model were constructed from clinical studies of aging in normal human subjects and of clinical glaucoma in patients to provide a direct comparison of the results from standard clinical perimetry and optical coherence tomography. The final formulation is a nonlinear structure-function model that was evaluated by the accuracy and precision of translating visual sensitivities in a region of the visual field to produce a predicted thickness of the retinal nerve fiber layer in the peripapillary sector that corresponded to the region of reduced visual sensitivity. The model was tested on two independent patient populations, with results that confirmed the predictive relationship between the retinal nerve fiber layer thickness and visual sensitivities from clinical perimetry. Thus, the proposed model for linking structure and function in glaucoma has provided information that is important in understanding the results of standard clinical testing and the neuronal losses caused by glaucoma, which may have clinical application for inter-test comparisons of the stage of disease.

Reaction time as a measure of suprathreshold grating detection

Abstract Simple reaction time measurements were made for a wide range of contrast values and spatial frequencies of sinusoidal gratings. For every spatial frequency, reaction time increased as the grating contrast decreased; however, over a range of spatial frequencies the contrast vs reaction time function was biphasic. Manipulations of stimulus duration, retinal location, and field size are consistent with two separate mechanisms for detecting gratings at high and low contrast levels within a mid-range of spatial frequencies. Perceptual “isocontrast” functions derived from the reaction time data show a consistent peak shift and shape change with variations in criterion reaction time.

Visual field defects and neural losses from experimental glaucoma

Glaucoma is a relatively common disease in which the death of retinal ganglion cells causes a progressive loss of sight, often leading to blindness. Typically, the degree of a patients visual dysfunction is assessed by clinical perimetry, involving subjective measurements of light-sense thresholds across the visual field, but the relationship between visual and neural losses is inexact. Therefore, to better understand of the effects of glaucoma on the visual system, a series of investigations involving psychophysics, electrophysiology, anatomy, and histochemistry were conducted on experimental glaucoma in monkeys. The principal results of the studies showed that, (1) the depth of visual defects with standard clinical perimetry are predicted by a loss of probability summation among retinal detection mechanisms, (2) glaucomatous optic atrophy causes a non-selective reduction of metabolism of neurons in the afferent visual pathway, and (3) objective electrophysiological methods can be as sensitive as standard clinical perimetry in assessing the neural losses from glaucoma. These experimental findings from glaucoma in monkeys provide fundamental data that should be applicable to improving methods for assessing glaucomatous optic neuropathy in patients.

Differential spectral photic damage to primate cones

Abstract Selective loss of sensitivity to blue and green parts of the spectrum following intermittent, repeated exposures to intense spectral lights persists longer than 3 yr following blue lights and between 18 and 40 days following green lights. The “blue-blindness” involves complete and sole loss of the response of the short-wavelength responsive cones. The “green-blindness” involves complete and sole loss of response of middle-wavelength sensitive cones. Histo-pathology of cones in a “blue-blinded” retina in comparison with cytochemical labeling of short-wavelength cones, reveals that they follow a similar distribution: are sparse in the foveola. reach a peak of about 16% of the cones near 1 and fall to 8–12% of the cones at 7. Continuous as distinct from intermittent exposures to similar blue lights produces a wholly different picture of gross pigment-epithelial damage with little photoreceptor degeneration.

Effects of optically induced blur on the refractive status of young monkeys

In each of eight rhesus monkeys, one eye was defocused with a -9 D contact lens beginning before 1 month of age for periods of 2-3 months. At the end of the rearing period, interocular comparisons showed that one subject had developed a relative axial myopia (3.0 D), however, five monkeys had developed a relative axial hyperopia (2.0-3.5 D). After discontinuing the contact-lens rearing procedure, the induced refractive errors diminished over time in all subjects. These results indicate that the defocus threshold for form-deprivation myopia is relatively high and that substantial levels of optical defocus which do not exceed this threshold typically produce axial hyperopia. The recovery data suggests that monkeys have an emmetropization mechanism which is sensitive to optical defocus, but the failure of this mechanism to compensate for the refractive errors simulated during the lens-rearing procedures suggests that this mechanism has a limited operating range.

Behavioral studies on the effect of abnormal early visual experience in monkeys: Spatial modulation sensitivity

Spatial modulation sensitivity functions have been investigated by behavioral methods in two monkeys reared with normal visual experience and 12 monkeys reared with abnormal, early visual experience. Experimental treatments were initiated when the animals were approximately one month of age. Two monkeys were each treated with one of the following procedures: (1) long-term monocular lid suture, (2) short-term monocular lid suture, (3) surgically induced esotropia, (4) surgically induced exotropia, (5) optical dissociation of binocular vision with ophthalmic prisms, or (6) chronic monocular cycloplegia. The results of the studies showed a severe loss of contrast sensitivity of the treated eyes compared to the control eyes for monkeys reared with monocular lid suture or surgically induced esotropia. Surgically induced exotropia resulted in a moderate reduction in sensitivity of the deviated eye while optical dissociation resulted in a mild reduction in sensitivity of one eye compared to the other. One of the two monkeys reared for seven months with chronic monocular cycloplegia had a relative reduction in contrast sensitivity of the treated eye, but the other monkey had equal sensitivities in the two eyes. However, binocular summation experiments showed that even though the relative difference between the monocular sensitivities was small or absent for the monkeys reared with optical dissociation or chronic monocular cycloplegia, none of them demonstrated binocular vision in these experiments.

Age-Related Losses of Retinal Ganglion Cells and Axons

PURPOSE Age-related losses in retinal nerve fiber layer (RNFL) thickness have been assumed to be the result of an age-dependent reduction of retinal ganglion cells (RGCs), but the published rates differ: age-related losses of RGCs of approximately 0.6%/year compared to 0.2%/year for thinning of the RNFL. An analysis of normative data for standard automated perimetry (SAP) sensitivities and optical coherence tomography (OCT) measures of RNFL thickness showed that the apparent disagreement in age-dependent losses of RGCs and axons in the RNFL can be reconciled by an age-dependent decrease in the proportion of the RNFL thickness that is composed of axons. The purpose of the present study was to determine whether the mechanisms of age-related losses that were suggested by the normative data can be confirmed with data from healthy, normal eyes. METHODS Data were obtained from visual fields (normal results in a Glaucoma Hemifield Test [GHT] on standard automated perimetry [SAP] 24-2 fields) and RNFL thickness measurements (standard OCT scan) of 55 patients (age range, 18-80 years; mean, 44.5 +/- 17.3). The SAP measures of visual sensitivity and OCT measures of RNFL thickness for one eye of each patient were used to estimate neuron counts by each procedure. RESULTS The age-related thinning of RNFL was 0.27%/year when a constant axon density was used to derive axon counts from RNFL thickness, compared with 0.50%/year for the age-related loss of RGCs from SAP. In agreement with the model developed with normative clinical data, concordance between losses of axons and soma was achieved by an age-dependent reduction of 0.46%/year in the density of axons in the RNFL. CONCLUSIONS The results suggest that the proportion of RNFL that is composed of RGC axons is not constant with age; rather, the proportion of the total thickness from non-neuronal tissue increases with age. If a similar compensation occurs in the RNFL thickness with axon loss from glaucoma, then a stage-dependent correction to translate OCT measurements to neuronal components is needed, in addition to the age-dependent correction.

Neuronal Responses in Visual Area V2 (V2) of Macaque Monkeys with Strabismic Amblyopia

Amblyopia, a developmental disorder of spatial vision, is thought to result from a cascade of cortical deficits over several processing stages beginning at the primary visual cortex (V1). However, beyond V1, little is known about how cortical development limits the visual performance of amblyopic primates. We quantitatively analyzed the monocular and binocular responses of V1 and V2 neurons in a group of strabismic monkeys exhibiting varying depths of amblyopia. Unlike in V1, the relative effectiveness of the affected eye to drive V2 neurons was drastically reduced in the amblyopic monkeys. The spatial resolution and the orientation bias of V2, but not V1, neurons were subnormal for the affected eyes. Binocular suppression was robust in both cortical areas, and the magnitude of suppression in individual monkeys was correlated with the depth of their amblyopia. These results suggest that the reduced functional connections beyond V1 and the subnormal spatial filter properties of V2 neurons might have substantially limited the sensitivity of the amblyopic eyes and that interocular suppression was likely to have played a key role in the observed alterations of V2 responses and the emergence of amblyopia.

Psychophysical evidence for sustained and transient channels in the monkey visual system

Abstract A number of electrophysiological studies have shown sustained and transient neurons in the monkey visual system. These findings are consistent with the large number of psychophysical experiments in which the data are best interpreted on the basis of sustained and transient channels in the human visual system. In the present study, three experimental procedures which have provided strong evidence for sustained and transient channels for human observers were replicated using 4 rhesus monkeys as subjects. All three procedures were based on detection of grating patterns generated on the CRT of an oscilloscope. Data were collected to obtain (1) reaction time distributions for near threshold contrast levels as a function of the spatial frequency of the gratings, (2) contrast sensitivity as a function of viewing duration for several spatial frequencies and (3) mean reaction time as a function of contrast for suprathreshold gratings. The reaction time histograms for near threshold stimuli showed a bimodal distribution of reaction times for low spatial frequencies and a unimodal distribution for higher spatial frequencies. The contrast sensitivity versus viewing duration curves showed that the slope of the function above a critical duration was nearly zero for low spatial frequencies and had a slope of approx 0.3 for higher spatial frequencies. The suprathreshold reaction time data showed a biphasic function for midrange spatial frequencies, but a monophasic function for high and low spatial frequencies. The data from all 3 experiments were consistent with similar data reported for human subjects and, therefore, to the extent that human data reflect the existence of sustained and transient channels, so do the monkey data.

Estimating the Rate of Retinal Ganglion Cell Loss in Glaucoma

PURPOSE To present and evaluate a new method of estimating rates of retinal ganglion cell (RGC) loss in glaucoma by combining structural and functional measurements. DESIGN Observational cohort study. METHODS The study included 213 eyes of 213 glaucoma patients followed up for an average of 4.5 ± 0.8 years with standard automated perimetry visual fields and optical coherence tomography. A control group of 33 eyes of 33 glaucoma patients underwent repeated tests over a short period to test the specificity of the method. An additional group of 52 eyes from 52 healthy subjects followed up for an average of 4.0 ± 0.7 years was used to estimate age-related losses of RGCs. Estimates of RGC counts were obtained from standard automated perimetry and optical coherence tomography, and a weighted average was used to obtain a final estimate of the number of RGCs for each eye. The rate of RGC loss was calculated for each eye using linear regression. Progression was defined by a statistically significant slope faster than the age-expected loss of RGCs. RESULTS From the 213 eyes, 47 (22.1%) showed rates of RGC loss that were faster than the age-expected decline. A larger proportion of glaucomatous eyes showed progression based on rates of RGC loss rather than based on isolated parameters from standard automated perimetry (8.5%) or optical coherence tomography (14.6%; P < .01), while maintaining similar specificities in the stable group. CONCLUSIONS The rate of RGC loss estimated from combining structure and function performed better than either isolated structural or functional measures for detecting progressive glaucomatous damage.