Shear modulus data for the human lens determined from a spinning lens test.

The paper describes a program of mechanical testing on donated human eye bank lenses. The principal purpose of the tests was to obtain experimental data on the shear modulus of the lens for use in future computational models of the accommodation process. Testing was conducted using a procedure in which deformations are induced in the lens by spinning it about its polar axis. Shear modulus data were inferred from these observed deformations by means of a finite element inverse analysis procedure in which the spatial variation of the shear modulus within the lens is represented by an appropriate function (see Burd et al., 2011 for a detailed specification of the design of the spinning lens test rig, experimental protocols and associated data analysis procedures that were employed in the tests). Inferred data on lens shear modulus are presented for a set of twenty-nine lenses in the age range 12 years to 58 years. The lenses were tested between 47 h and 110 h from the time of death (average post-mortem time 74 h). Care was taken to exclude any lenses that had been affected by excessive post-mortem swelling, or any lenses that had suffered mechanical damage during storage, transit or the testing process. The experimental data on shear modulus indicate that, for young lenses, the cortex is stiffer than the nucleus. The shear modulus of the nucleus and cortex both increase with increasing age. The shear modulus of the nucleus increases more rapidly than the cortex with the consequence that from an age of about 45 years onwards the nucleus is stiffer than the cortex. The principal shear modulus data presented in the paper were obtained by testing at a rotational speed of 1,000 rpm. Supplementary tests were conducted at rotational speeds of 700 rpm and 1,400 rpm. The results from these supplementary tests are in good agreement with the data obtained from the principal 1,000 rpm tests. Studies on the possible effects of lens drying during the test suggested that this factor is unlikely to have led to significant errors in the experimental determination of the shear modulus. The shear modulus data presented in the paper are used to develop 'age-stiffness' models to represent the shear modulus of the lens as a function of age. These models are in a form that may be readily incorporated in a finite element model of the accommodation process. A comparison is attempted between the shear modulus data presented in the current paper and equivalent data published by previous authors. This comparison highlights various limitations and inconsistencies in the data sets.

An improved spinning lens test to determine the stiffness of the human lens.

It is widely accepted that age-related changes in lens stiffness are significant for the development of presbyopia. However, precise details on the relative importance of age-related changes in the stiffness of the lens, in comparison with other potential mechanisms for the development of presbyopia, have not yet been established. One contributing factor to this uncertainty is the paucity and variability of experimental data on lens stiffness. The available published data generally indicate that stiffness varies spatially within the lens and that stiffness parameters tend to increase with age. However, considerable differences exist between these published data sets, both qualitatively and quantitatively. The current paper describes new and improved methods, based on the spinning lens approach pioneered by Fisher, R.F. (1971) 'The elastic constants of the human lens', Journal of Physiology, 212, 147-180, to make measurements on the stiffness of the human lens. These new procedures have been developed in an attempt to eliminate, or at least substantially reduce, various systematic errors in Fisher's original experiment. An improved test rig has been constructed and a new modelling procedure for determining lens stiffness parameters from observations made during the test has been devised. The experiment involves mounting a human lens on a vertical rotor so that the lens spins on its optical axis (typically at 1000 rpm). An automatic imaging system is used to capture the outline of the lens, while it is rotating, at pre-determined angular orientations. These images are used to quantify the deformations developed in the lens as a consequence of the centripetal forces induced by the rotation. Lens stiffness is inferred using axisymmetric finite element inverse analysis in which a nearly-incompressible neo-Hookean constitutive model is used to represent the mechanics of the lens. A numerical optimisation procedure is used to determine the stiffness parameters that provide a best fit between the finite element model and the experimental data. Sample results are presented for a human lens of age 33 years.

Trichloroethylene and its metabolite TaClo lead to degeneration of substantia nigra dopaminergic neurones: Effects in wild type and human A30P mutant α-synuclein mice.

Parkinson's disease (PD) is characterised pathologically by degeneration of the dopaminergic (DA) neurones of the substantia nigra pars compacta (SNpc) and the presence of α-synuclein containing Lewy body inclusions. Trichloroethylene (TCE) has been suggested as a potential environmental chemical that may contribute to the development of PD, via conversion to the neurotoxin, 1-Trichloromethyl-1,2,3,4-tetrahydro-ß-carboline (TaClo). We investigated the effect of an 8 week exposure to TCE or TaClo on wild type and, as an experimental model of PD, A30P mutant α-synuclein overexpressing mice using a combination of behaviour and pathology. TCE or TaClo exposure caused significant DA neuronal loss within the SNpc in both wild type and transgenic mice. Cell numbers were lower in A30P animals than wild type, however, no additive effect of TCE or TaClo exposure and A30P overexpression was found. TCE or TaClo did not appear to lead to acceleration of motor or cognitive deficits in either wild type or A30P mutant mice, potentially because of the modest reductions of DA neuronal number in the SNpc. Our results do however suggest that TCE exposure could be a possible factor in development of PD like changes following exposure.

Reflection makes sense of rotation of the eyes.

Our 3-D percept of the world is constructed from the two-dimensional visual images on the retina of each eye, but these images and the relationships between them are affected by the 3-D rotations of each eye. These 3-D eye rotations are constrained to patterns such as Listing's law, or its generalisation 'L2', according to the context. Our understanding of the patterns of such three-dimensional eye rotations, and their effect on the retinal images, has been greatly advanced by the development of algebraic methods (Haustein, 1989; Tweed & Vilis, 1987; Westheimer, 1957) for calculating the effect of eye rotations. But not many would say, with Dirac, that they understand the equations describing the 3-D geometry in the sense that they have "a way of figuring out the characteristic of its solution without actually solving it" (Dirac, according to Feynman, Leighton, & Sands, 1964). I show here how the geometry of 3-D rotations of the eye and their visual effects can be made easier to understand by use of the principle that a rotation through angle alpha can be achieved by a pair of reflections in planes with an angular separation alpha/2, and a common line that is the rotation axis (Tweed, 1997b; Tweed, Cadera, & Vilis, 1990). Mathematically (see Appendix A), the method is equivalent to decomposing the unit quaternions so successfully used to study three-dimensional eye rotations (Tweed & Vilis, 1987; Westheimer, 1957) into pairs of pure quaternions (ones whose scalar part is zero) which represent the reflections (Coxeter, 1946).

Can reliable values of Young's modulus be deduced from Fisher's (1971) spinning lens measurements?

The current textbook view of the causes of presbyopia rests very largely on a series of experiments reported by R.F. Fisher some three decades ago, and in particular on the values of lens Young's modulus inferred from the deformation caused by spinning excised lenses about their optical axis (Fisher 1971) We studied the extent to which inferred values of Young's modulus are influenced by assumptions inherent in the mathematical procedures used by Fisher to interpret the test and we investigated several alternative interpretation methods. The results suggest that modelling assumptions inherent in Fisher's original method may have led to systematic errors in the determination of the Young's modulus of the cortex and nucleus. Fisher's conclusion that the cortex is stiffer than the nucleus, particularly in middle age, may be an artefact associated with these systematic errors. Moreover, none of the models we explored are able to account for Fisher's claim that the removal of the capsule has only a modest effect on the deformations induced in the spinning lens.

Activity of neurones in the inferotemporal cortex of the alert monkey.

The activity of neurones in the inferotemporal cortex of the alert rhesus monkey was recorded while the monkey was shown visual stimuli, which included both food and non-food objects for comparison with the activity of neurones in the lateral hypothalamus and substantia innominata. In the anteroventral part of the inferotemporal cortex, neurones were found with visual responses which were sustained while the animal looked at the appropriate visual stimuli. The latency of the responses was 100 msec or more. The majority (96/142 or 68%) of these neurones responded more strongly to some stimuli than to others. These units usually had different responses when objects were shown from different views, and physical factors such as shape, size, orientation, colour and texture appeared to account for the responses of some of these units. Association of visual stimuli with a food reward (glucose solution) or an aversive taste (5% saline solution) did not affect the magnitude of the responses of the neurones to the stimuli either during the learning or after the period of learning. Nor did feeding the monkey to satiety affect the responses of the neurones to their effective stimuli.

Do target angular size-change and blur cues interact linearly in the control of human accommodation?

Calculations made using the data of Kruger and Polar [J. opt. Soc. Am. A2, 1832-1835 (1985); Vision Res. 26, 957-971 (1986); Vision Res. 27, 555-567 (1987)] show that for three of the four subjects they studied, size-change and blur cues do not interact linearly in the control of accommodation. A simple non-linear interaction model is shown to fit the data for all four subjects.

Ocular development and visual deprivation myopia in the common marmoset (Callithrix jacchus).

The normal postnatal ocular development of the common marmoset (Callithrix jacchus) and the effects of visual deprivation on eye growth and refractive state are described. The marmoset normally undergoes a developmental process of emmetropization from high hyperopia at birth. This emmetropization is easily disrupted by visual deprivation produced by lid-suture. Myopia and axial elongation of the vitreous chamber are induced by visual deprivations of 12, 5, and 3 weeks duration. The development of axial myopia after 3 weeks of visual deprivation differs from longer duration deprivations in that the experimental eyes are initially shorter than normal and hyperopic at the end of the visual deprivation period, but subsequently become longer than normal and myopic. Visual deprivation myopia in the marmoset persists even after the deprivation is discontinued and a visual signal is restored. In all experimental groups, the development of the eye in response to the cessation of visual deprivation shows no slowing of vitreous chamber enlargement; the axial enlargement relative to the control eye is either maintained or increases and produces significantly greater myopia. These results suggest that the visual control of postnatal eye growth in the marmoset may be unidirectional in its response to visual experience and able only to increase the growth rate of the vitreous chamber, possibly after an initial delay.

Overnight lens removal avoids changes in refraction and eye growth produced by plano soft contact lenses in infant marmosets.

Infant marmosets were fitted with zero-powered (plano) soft contact lenses from 4 to 8 weeks of age worn either continuously (24 h per day) (n = 4), for 12 h (n = 4), or for 8 h (n = 3) per day to determine whether limiting the daily duration of lens-wear could significantly reduce or eliminate the effects of continuous lens-wear on ocular growth and refractive state. As in macaques (Hung, L. F., & Smith, E. L. (1996). Extended-wear, soft, contact lenses produce hyperopia in young monkeys. Optometry and Vision Science, 73, 579-584), eyes fitted with contact lenses worn continuously developed more hyperopic refractions (mean +3.22 +/- 1.49 D SE) compared to their fellow untreated eyes, inconsistent changes in vitreous chamber depth (-0.02 +/- 0.09 mm SE) and flatter corneas (mean decrease in corneal power 4.22 +/- 0.39 D SE). Eyes wearing lenses for only 12 h per day showed similar but reduced effects compared to the 24-h group. Most importantly, ocular growth, corneal power and refraction were unaffected in the 8-h group. Future studies using contact lenses in infant primates should employ a reduced daily duration of lens-wear to eliminate the undesirable effect of contact lens-wear per se on ocular development.

Compensatory changes in eye growth and refraction induced by daily wear of soft contact lenses in young marmosets.

Several studies have shown that growth of the primate eye responds in a compensatory direction to both positive and negative spectacle lenses--eyes grow more slowly and become hyperopic in response to positive lenses, and eyes grow more rapidly and become myopic in response to negative lenses. On the other hand, extended wear soft contact lenses, whether positively or negatively powered, induce hyperopia (Hung & Smith, 1996. Extended-wear, soft, contact lenses produce hyperopia in young monkeys. Optometry & Vision Science 73, 579-584.). We investigated whether responses in a compensatory direction occurred to soft contact lenses worn on a daily wear basis (8 h per day on an 8:16 h light:dark cycle). Ten infant marmosets (8-13 weeks of age) wore a soft contact lens, in one eye only, for 5-9 weeks. Lens powers used were zero (n = 2), +2 D (n = 1), +2 D followed after 5 weeks of lens wear by +4 D (n = 1) for 4 weeks, +4 D (n = 2), -2 D followed after 5 weeks of lens wear by -4 D (n = 2) for 4 weeks, -4 D (n = 2). At the end of the lens-wear period the positive lens-wearing eyes were more hyperopic relative to the fellow untreated eyes [mean +2.39 +/- 0.24 D (SE)] and the negative lens-wearing eyes were more myopic than the fellow untreated eyes [mean -2.48 +/- 0.91 D (SE)]. Fellow eyes were unaffected by lens wear [mean final refraction +0.45 +/- 0.09 D (SE)]. Plano lenses did not affect eye growth in either marmoset fitted with plano contact lenses.

Normal development of refractive state and ocular component dimensions in the marmoset (Callithrix jacchus).

Refractive state and ocular dimensions were studied longitudinally in nine normal marmosets. Animals were anaesthetised and examined (with some exceptions) at 4, 6, 7, 8, 10, 15, 24 and 39 weeks of age. Cycloplegic retinoscopy showed that hyperopia early in life rapidly diminished. Refraction corrected for the artefact of retinoscopy stabilised by 8 weeks of age, but at a slightly myopic value, rather than at emmetropia. The ocular components continued to change throughout the period studied. Corneal radius, measured by photokeratometry, increased slightly during development. Anterior segment depth and vitreous chamber depth (VCD), measured by A-scan ultrasonography, increased throughout development while lens thickness initially increased and then decreased. Data from the eyes of these normal animals were compared with that from the contralateral eyes of animals which received short periods of monocular deprivation early in life (Troilo, D., & Judge S.J. (1993). Ocular development and visual deprivation myopia in the common marmoset (Callithrix jacchus jacchus). Vision Research, 33, 1311-24); eyes which viewed through no lens or a plano lens (Graham, B. & Judge, S.J. (1999)). The effects of spectacle wear in infancy on eye growth and refractive error in the marmoset (Callithrix jacchus). Vision Research, 39, 189-206), and eyes of normal animals in another colony. There were no significant differences between the first two groups and the normal animals in our colony while age-matched animals from the other colony were slightly but significantly less myopic than our animals.

The effects of spectacle wear in infancy on eye growth and refractive error in the marmoset (Callithrix jacchus).

We made a comprehensive study, involving observations on 45 marmosets, of the effects on ocular growth and refraction of wearing spectacles from the ages of 4-8 weeks. This period was within the period early in life when the eye grows rapidly and refraction changes from hyperopia to its adult value of modest myopia. In one series of experiments we studied the effect of lenses of powers -8, -4, +4 and +8D fitted monocularly. In another series of experiments we studied the effect of lenses of equal and opposite powers fitted binocularly, with the two eyes alternately occluded, so as to give an incentive to use both eyes, and in particular to accommodate, for at least part of each day, through the negative lens. The vitreous chamber of eyes that wore negative lenses of -4D or -8D, combined with alternate occlusion, elongated more rapidly than that of the fellow eye (negative lens eye-positive lens eye, 0.21 +/- 0.03 mm (S.E.M.), P < 0.01 and 0.25 +/- 0.06 mm, P < 0.05, respectively) and became relatively more myopic (2.8 +/- 0.26D, P < 0.01 and 2.4 +/- 0.61D, P < 0.05 respectively). Eyes that wore -4D lenses monocularly elongated more rapidly and became myopic than fellow eyes. Eyes that wore +4D or +8D lenses were less strongly affected: animals that wore +8D lenses monocularly (without alternate occlusion) developed a slight relative hyperopia (0.99 +/- 0.21D, P < 0.01), with the more hyperopic eyes also slightly shorter (0.09 +/- 0.05 mm) than their fellow eyes, but eyes wearing +4D lenses were not significantly different from their fellow eyes. Animals that wore -8D lenses monocularly (without alternate occlusion) developed a slight relative hyperopia after three weeks of lens-wear (0.85 +/- 0.26D, P < 0.05). These were the only eyes that responded in a non-compensatory direction to the optical challenge of spectacle wear, and we interpret this effect as one due to visual deprivation. After the removal of lenses, the degree of anisometropia slowly diminished in those groups of animals in which it had been induced, but in the three groups in which the largest effects had been produced by lens-wear the overall mean anisometropia (0.68 +/- 0.24D, P < 0.01) and vitreous chamber depth (VCD) discrepancy (0.09 +/- 0.03 mm, P < 0.01) were still significant at the end of the experiments, when the animals were 273 days old. The reduction of anisometropia in these groups was associated with an increase in the rate of elongation of the vitreous chamber in the eyes that had previously grown normally i.e. the less myopic eyes grew more rapidly than their fellow eyes: in the seven weeks following lens-wear these eyes became more myopic and longer than normal eyes (refraction P < 0.001; VCD P < 0.001). Control experiments showed that occlusion of one eye for 50% of the day had no effect on eye growth and refraction, and therefore that alternate occlusion itself had no effect.

Visual optics and retinal cone topography in the common marmoset (Callithrix jacchus).

The common marmoset (Callithrix jacchus) is a small, diurnal, New World monkey amenable to vision research. In this paper we describe the visual optics and cone photoreceptor topography of the normal adult marmoset. Paraxial optical ray-tracing shows that the marmoset eye is well represented as a scaled-down version of the human eye. The density of foveal and perifoveal cone photoreceptors in the marmoset is as high, and in peripheral retina higher, than those reported in humans and macaques. The foveal acuity predicted by the Nyquist limits set by the cone mosaic (30 c/deg) is in agreement with behavioral measures of visual acuity. Foveal depth of focus is remarkably small (< 0.2 D) for an eye of this size (axial length about 11 mm). Estimates of the amplitude of accommodation using infrared photorefraction indicate that the marmoset is capable of more than 20 D of accommodation.

Numerical modelling of the accommodating lens.

Data on geometric and material properties of the human lens derived from various published sources are used to construct axisymmetric, large displacement, finite element models of the accommodating lens of subjects aged 11, 29 and 45 years. The nucleus, cortex, capsule and zonule are modelled as linearly elastic materials. The numerical model of the 45-year lens is found to be significantly less effective in accommodating than the 29-year lens, suggesting that the modelling procedure is capable of capturing at least some of the features of presbyopia. The model of the 11-year lens shows some anomalous behaviour, and reasons for this are explored.

Mechanics of accommodation of the human eye.

The classical Helmholtz theory of accommodation has, over the years, not gone unchallenged and most recently has been opposed by Schachar at al. (1993) (Annals of Ophthalmology, 25 (1) 5-9) who suggest that increasing the zonular tension increases rather than decreases the power of the lens. This view is supported by a numerical analysis of the lens based on a linearised form of the governing equations. We propose in this paper an alternative numerical model in which the geometric non-linear behaviour of the lens is explicitly included. Our results differ from those of Schachar et al. (1993) and are consistent with the classical Helmholtz mechanism.

AMPA and NMDA receptor regulation of firing activity in 5-HT neurons of the dorsal and median raphe nuclei.

The glutamatergic regulation of 5-hydroxytryptamine (5-HT) neuronal activity has not been extensively studied. Here, we used extracellular single unit recording in midbrain slices to examine glutamate receptor mediated effects on 5-HT neuronal activity in the dorsal raphe nucleus (DRN) and the median raphe nucleus (MRN). Alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA; 1 and 3 microm) concentration-dependently increased firing in 5-HT neurons in both the DRN and the MRN. The response to AMPA was blocked by the AMPA receptor antagonist, 6,7-dinitroquinoxaline-2,3(1H-4H)-dione (DNQX; 10 microm) but not the N-methyl-d-aspartate (NMDA) receptor antagonist, 2-amino-5-phosphonopentanoic acid (AP-5; 50 microm). NMDA (10-100 microm) also increased 5-HT neuronal firing in a concentration-dependent manner in both the DRN and MRN; a response that was blocked by AP-5 (50 microm). In some DRN neurons the NMDA response was partially antagonized by DNQX (10 microm) suggesting that NMDA, as well as directly activating 5-HT neurons, evokes local release of glutamate, which indirectly activates AMPA receptors on 5-HT neurons. Responses of DRN 5-HT neurons to AMPA and NMDA were enhanced by the gamma-amino-butyric acid (GABA)(A) receptor antagonist, bicuculline (50 microm), suggesting that both AMPA and NMDA increase local release of GABA. Finally in the DRN the 5-HT(1A) receptor antagonist, WAY100635 (100 nm), failed to enhance the response of 5-HT neurons to AMPA and caused only a small increase in the excitatory response to NMDA suggesting a low degree of tonic activation of 5-HT(1A) autoreceptors even when 5-HT neuronal firing rate is high.

How is binocularity maintained during convergence and divergence?

The geometrical requirements for binocular fusion are stated, and the main features of horizontal vergence eye movements are described, together with an influential schema of understanding the interaction between vergence and accommodation. The anatomy and physiology of the midbrain region implicated in vergence and accommodation control are discussed. The cortical areas from which suitable sensory signals might be derived are mentioned briefly, and a speculation is made about esotropia.

Optically-induced changes in tonic vergence and AC/A ratio in normal monkeys and monkeys with lesions of the flocculus and ventral paraflocculus.

Monkeys wore either base-out prisms to promote changes in tonic vergence or periscopic spectacles to promote changes in the coupling between accommodation and vergence. Eye movements were recorded using the magnetic search coil technique and the monkeys were rewarded for accurate fixation. Two normal monkeys and two monkeys which had previously received lesions of the flocculus and ventral paraflocculus were studied. After 30 min of prism viewing the two normal monkeys had elevated phoria--increased by approximately 50% of the prism stimulus. The two lesioned monkeys also had phoria increases of a similar size after prism viewing. The effect of duration of prism viewing on the magnitude and time course of phoria elevation was studied in one normal monkey. The initial magnitude of phoria elevation and the time constant of relaxation of phoria both increased as the duration of prism exposure varied from 5 s to 30 min. Initial phoria increased approximately in proportion to the logarithm of duration of prism exposure whereas the time constant of phoria relaxation increased linearly with duration. In the same normal monkey it was shown that increasing vergence by means of accommodative-vergence did not induce phoria changes. The effect of periscopic spectacle viewing was studied in all four monkeys. After 30 min of periscopic spectacle viewing all four monkeys had a higher AC/A ratio. The magnitude of the changes was (paradoxically) greater in the two lesioned monkeys than in the one normal monkey studied fully.(ABSTRACT TRUNCATED AT 250 WORDS)